2-substituted cephem compounds

ABSTRACT

The present invention relates to 2-substituted cephem compounds of Formula (I) having a quaternary ammonium group on the 3-side chain, preferably together with a cathechol group, or pharmaceutically acceptable salts thereof, which exhibit potent antimicrobial spectrum against a variety of bacteria including Gram negative bacteria and/or Gram positive bacteria, corresponding pharmaceutical compositions, methods of making, treatment methods for bacterial infections or uses thereof.

TECHNICAL FIELD

The compounds of the subject invention are related to 2-substitutedcephem compounds, which have a wide antimicrobial spectrum, inparticular exhibit potent antimicrobial activity against beta-lactamaseproducing Gram negative bacteria, and pharmaceutical compositionscomprising the same.

BACKGROUND

To date, a variety of beta-lactam drugs have been developed andbeta-lactam drugs have become clinically extremely importantantimicrobial drugs. However, there are increasing number of bacterialtypes which have obtained resistance against beta-lactam drugs byproducing beta-lactamase, which degrade beta-lactam drugs.

According to the Ambler molecular classification, beta-lactamases arelargely classified into four classes. Specifically, these are Class A(TEM type, SHV type, CTX-M type, KPC type and the like), Class B (IMPtype, VIM type, L-1 type and the like), Class C (AmpC type) and Class D(OXA type and the like). Amongst these, Classes A, C and D types arelargely classified into serine-beta-lactamase, on the other hand, ClassB type is classified into metallo-beta-lactamase. It has been known thatboth have respectively different mechanisms to each other in terms ofhydrolysis of beta-lactam drugs.

Recently, clinical problem has been occurring due to the existence ofGram negative bacteria which have become highly resistant to a number ofbeta-lactam drugs including Cephems and Carbapenems by producing Class A(ESBL) and D types serine-beta-lactamases which have an extendedsubstrate spectrum, and Class B type metallo-beta-lactamase which havean extended substrate spectrum. Particularly, metallo-beta-lactamase isknown to be one of the causes of obtaining multidrug-resistance in Gramnegative bacteria. Cephem compounds which exhibit intermediate activityagainst metallo-beta-lactamase producing Gram negative bacteria areknown (e.g., International Publication No. 2007/119511 pamphlet andApplied Microbiology and Biotechnology (1994), 40(6), 892-7). However,there is a demand for development of Cephem compounds which exhibit morepotent antimicrobial activity, in particular more effective against avariety of beta-lactamase producing Gram negative bacteria.

One of the known antimicrobials having high anti-Gram negativebactericidal activity is Cephem compounds having a catechol groupintramolecularly (e.g., The Journal of Antibiotics, vol. 61, pp. 36-39(2008); The Journal of Antibiotics, vol. 43, pp. 1617-1620 (1990) TheJournal of Antibiotics, vol. 42, pp. 795-806 (1989)). The action thereofis that the catechol group forms a chelate with Fe³⁺, thereby thecompound is efficiently incorporated into the bacterial body through theFe³⁺ transportation system on the cellular membrane (tonB-dependent irontransport system). Therefore, research has been conducted on compoundshaving catechol or similar structure thereto, on the 3-side chain or7-side chain moiety on the Cephem backbone.

Examples in the non-patent literature (i.e., e.g., see, AppliedMicrobiology and Biotechnology (1994), 40(6), 892-7) and patentliterature (i.e., see Japanese Laid-Open Publication No. 4-364189;Japanese Laid-Open Publication No. 3-173893; Japanese Laid-OpenPublication No. 2-15090; Japanese Laid-Open Publication No. 2-28187;Japanese Laid-Open Publication No. 2-117678; Japanese Laid-OpenPublication No. 2-28185), respectively, describe catechol typederivatives having a catechol group on the 3-side chain moiety on theCephem backbone. Other patent documents (i.e., e.g., Japanese Laid-OpenPublication No. 2-15090; Japanese Laid-Open Publication No. 2-28187;Japanese Laid-Open Publication No. 6-510523; and Japanese Laid-OpenPublication No. 5-213971) describe pseudo-catechol type derivativeshaving a hydroxypyridone group on the 3-side chain moiety on the Cephembackbone. Patent Documents, International Publication No. 2007/096740pamphlet and International Publication No. 2003/078440 pamphlet discloseCephem compounds having a quaternary ammonium group, but do not describea catechol type derivative.

Moreover, in the above documents, which describe Cephem compounds havinga catechol group in their structure, there is no description of Class Btype metallo-beta-lactamase and specific antimicrobial activity againsta wide variety of Gram negative bacteria including Class B type.

Additionally, specific patent literature documents (i.e., e.g., EuropeanPatent Publication No. 35357 and U.S. Pat. No. 3,487,079) and non-patentliterature documents (i.e., e.g., Chemical & Pharmaceutical Bulletin,vol. 31, 1482-1493 (1983); Journal of Medicinal Chemistry, vol. 14,420-425 (1971); and International Journal of Peptide & Protein Research,vol. 10, 51-59 (1977)), respectively, describe cephem compounds having asubstituent at position 2 of the cephem skeleton. However, thesecompounds do not have a quaternary ammonium group and a cathechol groupat position 3 of the cephem skeleton.

Non-patent literature (e.g., The Journal of Antibiotics, vol. 41, pp.1154-1157 (1988); The Journal of Antibiotics, vol. 43, pp. 357-371(1989)) describe oxa-cephem compounds having a substituent at position 2of the oxa-cephem skeleton. However, these compounds do not have acathechol group at position 3 of the oxa-cephem skeleton.

The present applicant has filed patent applications of cephem compoundshaving catechol type substituents (e.g., International Publication No.2010/050468 pamphlet; International Publication No. 2011/125966pamphlet; International Publication No. 2011/125967 pamphlet andInternational Publication No. 2011/136268 pamphlet). However, theseapplications do not disclose a compound having a substituent at position2 of the cephem skeleton.

SUMMARY OF INVENTION Problems to be Solved by the Invention

The subject invention provides 2-substituted cephem compounds having aquaternary ammonium group on the 3-side chain, preferably together witha cathechol group, which exhibit potent antimicrobial spectrum against avariety of bacteria including Gram negative bacteria and/or Grampositive bacteria. Preferably, the compounds are effective againstbeta-lactamase producing Gram negative bacteria, includingmultidrug-resistant bacteria, in particular, Class B typemetallo-beta-lactamase producing Gram negative bacteria, andextended-spectrum beta-lactamase (ESBL) producing bacteria. Furthermore,the subject invention provides preferably cephem compounds havingantimicrobial activity against strains resistant to 2-unsubstitutedcephem compounds.

Means for Solving the Problem

The subject invention provides cephem compounds which have solved theabove-mentioned problems with the following structural characteristics:

1) a substituent group(s) at the position 2, preferably an alkyl group.

2) a quaternary ammonium group on the 3-side chain.

3) a cathechol group at the terminal or in the quaternary ammonium groupof the 3-side chain as a preferable embodiment.

The subject invention provides the following inventions:

1. A compound of the formula (I):

an ester at carboxyl group, an amino-protected compound when the aminois present on a ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof,wherein,

R¹ is an optionally substituted carbocyclic group or an optionallysubstituted heterocyclic group;

with regard to R^(2A) and R^(2B),

a) R^(2A) is hydrogen, optionally substituted amino, —SO₃H, optionallysubstituted amino sulfonyl, carboxyl, optionally substituted (loweralkyl)oxycarbonyl, optionally substituted carbamoyl, hydroxyl, orsubstituted carbonyloxy; and R^(2B) is hydrogen, provided that R^(2A)and R^(2B) are not hydrogen at the same time, or

b) R^(2A) and R^(2B) are taken together to form optionally substitutedmethylidene or optionally substituted hydroxyimino;

R³ is hydrogen, —OCH₃ or —NH—CH(═O);

with regard to R^(5A) and R^(5B),

a) R^(5A) and R^(5B) are each independently hydrogen, or lower alkyl andR^(5A) and R^(5B) are not hydrogen at the same time,

b) R^(5A) and R^(5B) may be taken together with the neighboring atom toform optionally substituted carbocycle or a optionally substitutedheterocyclic group, or

c) R^(5A) and R^(5B) may be taken together to form optionallysubstituted methylidene;

L is —CH₂—, —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —S—, —CH₂—S—, —CH═CH—S—or —CH═CH—CH₂—S—;

E is an optionally substituted divalent group having at least onequaternary ammonium ion;

R¹⁰ is hydrogen or a group represented by the formula (I-B)

wherein,

ring A is a benzene ring, monocyclic heterocycle or fused heterocycle;

n is an integer from 0 to 2;

each R⁴ is independently hydrogen, halogen, oxo, —OH, —CN, —NO₂,—O—C(═O)—R⁹, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR^(9′), —NR⁹R⁹, —SO₂R⁹,—SR⁹, —NR⁹—C(═O)—R⁹, optionally substituted lower alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; provided that two hydroxyl groups on ring A bindrespectively to carbon atoms each adjacently locates;

each R⁹ is independently lower alkyl or halo(lower)alkyl;

G is a single bond, optionally substituted lower alkylene, optionallysubstituted alkenylene or optionally substituted alkynylene;

B is non-existent, a single bond or a 5- or 6-membered heterocyclicgroup containing at least 1-3 nitrogen atoms;

D is non-existent, a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—,—NR⁶—C(═O)—, —C(═O)—NR⁶—, —C(═O)—C(═O)—, —NR⁶—C(═O)—NR⁶—,—C(═O)—C(═O)—NR⁶—, —C(═O)—NR⁶—C(═O)—, —NR⁶—C(═O)—C(═O)—,—NR⁶—NR⁶—C(═O)—, —C(═O)—NR⁶—NR⁶—, —N═N—C(═O)—, —C(═O)—N═N—,—C═N—NR⁶—C(═O)—, —C═N—C(═O)—, —N═C—C(═O)—, —C═N—C(═O)—NR⁶—,—NR⁶—C(═O)—C(═N—OR⁶)—, —C(═N—OR⁶)—C(═O)—NR⁶—, —NR⁶—, C(═N—OR⁶)—,—C(═N—OR⁶)—NR⁶—, —C(═O)—C(═N—OR⁶)—, —C(═N—OR⁶)—C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—NR⁶—, —NR⁶—S(═O)₂—, —NR⁶—CH₂—, —CH₂—NR⁶— or —S(═O)₂—;

each R⁶ is independently hydrogen or optionally substituted lower alkyl;

provided that when R¹⁰ is hydrogen, E is an optionally substituteddivalent cyclic group having at least one quanternary ammonium ion andat least two hydroxyl groups which bind respectively to carbon atomseach adjacently locates on the cyclic group.

In one aspect of the present invention Formula (I-B) is defined asfollows:

where:

ring A is defined as a fused heterocycle ring system comprised of atleast two (2) rings fused together;

where:

R⁴ optionally is substituted on each of the at least two (2) rings ofthe fused heterocycle ring system defined as ring A, such that each R4substituent on each ring of the fused heterocycle ring systemindependently are selected from identical or different substituents;

where:

-   -   each R⁴ as defined above optionally is substituted independently        on each ring of the fused heterocycle ring is selected from        hydrogen, halogen, oxo, —OH, —CN, —NO₂, —O—C(═O)—R⁹, —C(═O)—R⁹,        —C(═O)—OH, —C(═O)—OR⁹, —OR^(9′), —NR⁹R⁹, —SO₂R⁹, —SR⁹,        —NR⁹—C(═O)—R⁹, optionally substituted lower alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, or        optionally substituted heteroaryl;        -   provided that two hydroxyl groups on ring A bind            respectively to carbon atoms each adjacently locates; and n            is an integer from 0 to 2.            2. The compound, an ester at carboxyl group, an            amino-protected compound when the amino is present on the            ring in the 7-side chain, or a pharmaceutically acceptable            salt thereof according to the above 1, wherein R^(5A) is            hydrogen and R^(5B) is lower alkyl.            3. The compound, an ester at carboxyl group, an            amino-protected compound when the amino is present on the            ring in the 7-side chain, or a pharmaceutically acceptable            salt thereof according to the above 1 or 2, wherein, R¹⁰ is            a group represented by the formula (I-B):

wherein, each symbol is as defined above in 1 and throughout the instantspecification.4. The compound, an ester at carboxyl group, an amino-protected compoundwhen the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 1, 2 or3, wherein, ring A is a benzene ring or monocyclic heterocycle.5. The compound, an ester at carboxyl group, an amino-protected compoundwhen the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 1, 2 or3, wherein, ring A is fused heterocycle or an optionally substitutedfused heterocycle, where each ring of the fused heterocycleindependently is substituted with identical or different substituents.

In one aspect, ring A as defined herein is a fused heterocycle ringsystem comprised of at least two (2) rings fused together optionallysubstituted by substituents selected from R⁴;

where:

R⁴ optionally is substituted on each of the at least two (2) rings ofthe fused heterocycle ring system defined as ring A, such that each R4substituent on each ring of the fused heterocycle ring systemindependently are selected from identical or different substituents;

where:

-   -   each R⁴ as defined above optionally is substituted independently        on each ring of the fused heterocycle ring is selected from        hydrogen, halogen, oxo, —OH, —CN, —NO₂, —O—C(═O)—R⁹, —C(═O)—R⁹,        —C(═O)—OH, —C(═O)—OR⁹, —OR^(9′), —NR⁹R⁹, —SO₂R⁹, —SR⁹,        —NR⁹—C(═O)—R⁹, optionally substituted lower alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, or        optionally substituted heteroaryl;        -   provided that two hydroxyl groups on ring A bind            respectively to carbon atoms each adjacently locates; and    -   n is an integer from 0 to 2.        6. The compound, an ester at carboxyl group, an amino-protected        compound when the amino is present on the ring in the 7-side        chain, or a pharmaceutically acceptable salt thereof according        to the above 1 or 2, wherein, R¹⁰ is hydrogen;        E is an optionally substituted divalent cyclic group having at        least one quanternary ammonium ion and at least two hydroxyl        groups which bind respectively to carbon atoms each adjacently        locates on the cyclic group.        7. The compound, an ester at carboxyl group, an amino-protected        compound when the amino is present on the ring in the 7-side        chain, or a pharmaceutically acceptable salt thereof according        to any one of the above 1 to 5, wherein, G is a single bond,        —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH═CH—, —CH═CH—CH₂—,        —CH₂—CH═CH—, —CH₂—CH(CH₃)—, —CH₂—CH(^(i)Pr)- or —CH₂—CH(Ph)-        wherein ^(i)Pr is isopropyl and Ph is phenyl.        8. The compound, an ester at carboxyl group, an amino-protected        compound when the amino is present on the ring in the 7-side        chain, or a pharmaceutically acceptable salt thereof according        to the above 1, 2, 3, 4, 5 or 7, wherein, B is non-existent, a        single bond or a group represented by the formula:

wherein, the bond of the left side is attached to G and the bond of theright side is attached to D.9. The compound, an ester at carboxyl group, an amino-protected compoundwhen the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 1, 2, 3,4, 5, 7 or 8,wherein, D is non-existent, a single bond, —C(═O)—, —O—C(═O)—,—C(═O)—O—, —NR⁶—, —O—, —C(═O)—C(═O)—, —NR⁶—C(═O)—NR⁶—,—C(═O)—C(═O)—NR⁶—, —C(═O)—NR⁶—C(═O)—, —NR⁶—C(═O)—C(═O)—, —NR⁶—C(═O)—,—C(═)—NR⁶—, —NR⁶—NR⁶—C(═O)—, —C(═O)—NR⁶—NR⁶—, —N═N—C(═O)—, —C(═O)—N═N—,—C═N—NR⁶—C(═O)—, —C═N—C(═O)—, —N═C—C(═O)—, —C═N—C(═O)—NR⁶—,—NR⁶—C(═O)—C(═N—OR⁶)—, —C(═N—OR⁶)—C(═O)—NR⁶—, —NR⁶—C(═N—OR⁶)—,—C(═O)—C(═N—OR⁶)—, —C(═N—OR⁶)—C(═O)— or —C(═N—OR⁶)—NR⁶—, wherein R⁶ isas defined in the above 1.

In one aspect, The compound, an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof according tothe above 1, 2, 3, 5, 7, 8 or 9, wherein, the formula I-C-1):

wherein:

ring A is defined as a fused heterocycle ring system comprised of atleast two (2) rings fused together;

where:

R⁴ optionally is substituted on each of the at least two (2) rings ofthe fused heterocycle ring system defined as ring A, such that each R4substituent on each ring of the fused heterocycle ring systemindependently are selected from identical or different substituents;

where:

-   -   each R⁴ as defined above optionally is substituted independently        on each ring of the fused heterocycle ring is selected from        hydrogen, halogen, oxo, —OH, —CN, —NO₂, —O—C(═O)—R⁹, —C(═O)—R⁹,        —C(═O)—OH, —C(═O)—OR⁹, —OR^(9′), —NR⁹R⁹, —SO₂R⁹, —SR⁹,        —NR⁹—C(═O)—R⁹, optionally substituted lower alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, or        optionally substituted heteroaryl;        -   provided that two hydroxyl groups on ring A bind            respectively to carbon atoms each adjacently locates; and    -   n is an integer from 0 to 2.        10. The compound, an ester at carboxyl group, an amino-protected        compound when the amino is present on the ring in the 7-side        chain, or a pharmaceutically acceptable salt thereof according        to the above 1, 2, 3, 4, 7, 8 or 9, wherein, the formula        (I-C-1):

is a group selected from the following formulae:

wherein, each R^(4a), R^(4b) and R^(4c) is independently hydrogen,halogen, —OH, —CN, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR⁹, optionallysubstituted lower alkyl, or optionally substituted cycloalkyl and R⁶ andR⁹ are as defined in the above 1,the wavy line means that the bond is in cis or trans configuration, or amixture thereof.11. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 10,wherein, the formula (I-C-1):

is a group selected from the following formulae:

wherein, R⁶ is hydrogen, methyl, ethyl, tert-buthyl, carboxymethyl,0.2-carboxypropan-2-yl or 1-carboxyethyl, the wavy line means that thebond is in cis or trans configuration, or a mixture thereof.12. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 1, 2, 3,5, 7, 8 or 9, wherein, the formula (I-C-1):

is a group selected from the following formulae:

wherein, each R^(4a), R^(4b) and R^(4d) is independently hydrogen,halogen, —OH, —CN, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR⁹, optionallysubstituted lower alkyl, or optionally substituted cycloalkyl and R⁶ andR⁹ are as defined in the above 1,13. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 12,wherein, the formula (I-C-1):

is a group selected from the following formulae:

14. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 13, wherein E is an optionally substituted, saturated orunsaturated, monocyclic or fused cyclic group having at least onequaternary ammonium ion represented by the formula (I-D):

wherein,

the dashed line is a bond in the ring;

the bond to the cationic nitrogen atom binds to L, and the other bondbinds to R¹⁰; provided,

when a cationic nitrogen atom binds to R¹⁰, the dashed line is absent,and

when a cationic nitrogen atom does not bind to R¹⁰, the dashed line is asingle bond between the cationic nitrogen atom and a neighboring atom oran alkylene group between the cationic nitrogen atom and a ring memberatom other than said neighboring atom.

15. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 13, wherein E is an optionally substituted, saturated orunsaturated, monocyclic or fused cyclic group having at least onequaternary ammonium ion represented by the formula (I-E):

wherein, the bond to the cationic nitrogen atom binds to L, and theother bond binds to R¹⁰; R^(x) is optionally substituted lower alkyl.16. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 13, wherein L is —S—, —CH₂—S—, —CH═CH—S— or —CH═CH—CH₂—S— andE is an optionally substituted pyridinium group or an optionallysubstituted fused pyridinium group.17. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 16, E isa group selected from the following formulae which are optionallysubstituted on the ring;

wherein the bond to the cationic nitrogen atom binds to R¹⁰, the otherbond binds to L.18. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 15, wherein E is a group selected from the following formulaewhich are optionally substituted on the ring:

wherein,

the bond to the quaternary nitrogen atom binds to L, and the other bondbinds to R¹⁰;

p is an integer from 1 to 3;

n is an integer of 1 or 2;

R^(x) is optionally substituted lower alkyl.

19. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 13,wherein, E is selected from the group consisting of the formulae (2),(3), (7), (10), (11), (26), (27), (41), (42), (59), (60) and (77).20. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 15, wherein E is a group selected from the following formulaewhich are optionally substituted on the ring:

wherein, the bond to the quaternary nitrogen atom binds to L, and theother bond binds to R¹⁰.21. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 20,wherein E-R¹⁰ is a group selected from the following formulae:

wherein, the bond to the quaternary nitrogen atom binds to L.22. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 21,wherein E-R¹⁰ is represented by the formula:

wherein, the bond to the quaternary nitrogen atom binds to L.23. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 16,wherein -L-E- is represented by the formula;

wherein, the bond to the quaternary nitrogen atom binds to R¹⁰, theother bond binds to cephem at 3 position.24. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 23, wherein R³ is hydrogen or —OCH₃.25. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 24, wherein R¹ is an optionally substituted phenyl.26. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 24, wherein R¹ is represented by the formula:

wherein, X is N, C(—H) or C(—Cl).27. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 26,wherein, X is N.28. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 26,wherein, X is C(—H) or C(—Cl).29. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 28, wherein, R^(2A) is hydrogen, optionally substitutedamino, —SO₃H, optionally substituted amino sulfonyl, carboxyl,optionally substituted carbamoyl, hydroxyl, or substituted carbonyloxy,and R^(2B) is hydrogen.30. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 29,wherein, R^(2A) is:substituted amino shown below:

substituted amino sulfonyl shown below:

wherein, ring B represents an optionally substituted heterocyclic group;substituted carbamoyl shown below:

wherein, ring B represents an optionally substituted heterocyclic group;orsubstituted carbonyloxy shown below:

wherein, ring B represents an optionally substituted heterocyclic group.31. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 29,wherein, R^(2A) and R^(2B) are taken together to form:substituted methylidene shown below:

substituted hydroxyimino shown below:

wherein, R⁹ is optionally substituted lower alkyl.32. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to any one of theabove 1 to 29, wherein R^(2A) and R^(2B) are taken together to formsubstituted hydroxyimino shown below:

wherein,

R⁷ and R⁸ are each independently hydrogen, halogen, hydroxyl, carboxyl,optionally substituted lower alkyl, an optionally substitutedcarbocyclic group, or an optionally substituted heterocyclic group, or

R⁷ and R⁸ may be taken together with a neighboring atom to form anoptionally substituted carbocyclic group or an optionally substitutedheterocyclic group;

Q is a single bond, an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; and m is an integer from 0 to3.

33. A compound of the formula (I-G-1):

an ester at carboxyl group, an amino-protected compound when the aminois present on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof according to any one of the above 1 to 24,wherein, each symbol is as defined above.34. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 33,wherein, R^(5A) is hydrogen and R^(5B) is lower alkyl; R¹⁰ is a grouprepresented by the formula (I-B);

each symbol is as defined above.35. The compound, an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to the above 34,wherein,

X is C(—H), C(—Cl) or N;

each R⁷ and R⁸ is independently hydrogen or lower alkyl;R3 is hydrogen;m is 0 or 1;Q is a single bond;L is —CH2-; E is a group selected from the following formulae;

wherein, Rx is lower alkyl, p is an integer from 1 to 3;G is a single bond or lower alkylene;B is a single bond;D is a single bond, —C(═O)—, —C(═O)—C(═O)—, —NR⁶—C(═O)—C(═O)—,—NR⁶—C(═O)— or —NH—C(═O)—C(═N—OR^(6a));R⁶ is hydrogen or lower alkyl;R^(6a) is hydrogen, methyl, carboxymethyl, or 2-carboxypropane-2-yl;the formula (1-B-2);

is a group selected from the following formulae;

wherein each R^(4a), R^(4b) and R^(4c) is independently hydrogen,halogen or lower alkyl; R^(4d) is hydrogen, lower alkyl or lowercycloalkyl.36. A pharmaceutical composition, which comprises a compound, an esterat carboxyl group, an amino-protected compound when the amino is presenton the ring in the 7-side chain, or a pharmaceutically acceptable saltthereof according to any one of the above 1 to 35.37. The pharmaceutical composition according to the above 36, whichpossesses antimicrobial activity.

Effects of the Invention

The compounds of the subject invention are useful as a pharmaceuticalproduct having at least one of the following features:

1) the compounds exhibit potent antimicrobial spectrum against a varietyof bacteria including Gram negative bacteria and/or Gram positivebacteria;

2) the compounds exhibit potent antimicrobial activity againstbeta-lactamase producing Gram negative bacteria;

3) the compounds exhibit potent antimicrobial activity againstmultidrug-resistant bacteria, in particular, Class B typemetallo-beta-lactamase producing Gram negative bacteria;

4) the compounds exhibit potent antimicrobial activity againstextended-spectrum beta-lactamase (ESBL) producing bacteria;

5) the compounds do not exhibit cross resistance with known cephem drugsand/or carbapenem drugs; and

6) the compounds do not exhibit side effects such as toxicity and feverafter administration into the body;

7) the compounds are stable for storage and/or well soluble in water;

8) the compounds of the present invention have excellent featuresregarding kinetics in the body, such as high blood concentration, highbioavailabity, long duration of effects, and/or high tissue migration;and

9) the compounds of the present invention also may exhibit or haveantimicrobial activity against biothreat organisms, which may include,but are not limited to those biothreat organisms, such as Yersiniapestis, Bacillus anthracis, Francisella tularensis, Burkholderia malleiBurkholderia pseudomallei, Brucella suis, Brucella melitensis orBrucella abortus.

Preferable Embodiments for Carrying Out the Invention

It should be understood that, throughout the present specification, theexpression of a singular form (e.g., “a”, “an”, “the”, and the like; andin other languages, corresponding articles, adjectives, and the like)includes the concept of its plural form unless specified otherwise.Furthermore, it should be understood that the terms used herein are usedin a meaning normally used in the art unless specified otherwise. Thus,unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those generally understood by those skilled inthe art in the field to which the subject invention pertains. Eachspecific definition of terms specifically used herein is describedbelow. Each term used herein means, alone or in combination with anotherword, as below.

“Halogen” includes fluoro, chloro, bromo and iodo. Preferably, halogenis fluoro, chloro or bromo, and more preferably is chloro.

“Lower alkyl” includes linear or branched alkyl having 1-8 carbons,preferably 1-6 carbons, and more preferably 1-4 carbons, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl,isoheptyl, n-octyl, and the like.

“Lower alkylene” includes linear alkylene having 1-8 carbons, preferably1-6 carbons, more preferably 1-4 carbons, and most preferably one or twocarbons, for example, methylene, ethylene, n-propylene, n-butylene,n-pentylene, n-hexylene, and the like.

“Lower alkenylene” includes linear alkenylene having 2-8 carbons,preferably 2-6 carbons, more preferably 2-4 carbons, and at least onedouble bond at any position, and includes, for example, vinylene,allylene, propenylene, butenylene, prenylene, butadienylene,pentenylene, pentadienylene, hexenylene, hexadienylene, and the like.

“Lower alkynylene” includes linear alkynylene having 2-8 carbons,preferably 2-6 carbons, more preferably 2-4 carbons, and at least onetriple bond at any position, for example, ethynylene, propynylene,buthynylene, pentynylene, hexynylene, and the like.

“Halo(lower)alkyl” refers to a group in which at least one position ofsaid “lower alkyl” is substituted with the above “halogen”, andincludes, for example, monofluoromethyl, difluoromethyl, ifluoromethyl,monochloromethyl, dichloromethyl, trichloromethyl, monobromomethyl,monofluoroethyl, monochloroethyl, chlorodifluoromethyl, and the like.Preferably is trifluoromethyl or trichloromethyl.

“Aralkyl” includes the above lower alkyl substituted with one to threegroups selected from “aryl” mentioned below, preferably wherein thecarbon number of alkyl is 1 to 4, more preferably is 1 or 2, forexample, benzyl, phenethyl, phenylpropyl, trityl, and the like.

“Heteroaralkyl” includes the above lower alkyl substituted with one tothree groups selected from “heteroaryl” mentioned below, preferablywherein the carbon number of alkyl is 1 to 4, more preferably is 1 or 2,for example, furylmethyl, thienylmethyl, pyrolylmethyl, pyridylmethyl,thienylethyl, furylethyl, imidazorylmethyl, benzotienylmethyl,thiazolylmethyl, and the like.

“Acyl” includes formyl, optionally substituted lower alkylcarbonyl(e.g., acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl,pivaloyl, hexanoyl, octanoyl, methoxyethylcarbonyl,2,2,2-trifluoroethylcarbonyl), optionally substituted alkenyloxycarbonyl(e.g., alloc, cinnamyloxy carbonyl), alkoxycarbonylacetyl (e.g.,ethoxycarbonylmethylcarbonyl), (lower)alkoxy(lower)alkylcarbonyl (e.g.,methoxyethylcarbonyl), (lower)alkylcarbamoyl(lower)alkylcarbonyl (e.g.,methylcarbamoylethylcarbonyl), optionally substituted arylcarbonyl(e.g., benzoyl, toluoyl), optionally substituted cycloalkyloxy carbonyl(e.g., cycrohexyloxycarbonyl), optionally substituted aralkyloxycarbonyl (e.g., benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), optionallysubstituted heteroaralkyl carbonyl (e.g., thienylmethyl carbonyl) andthe like.

Substituents of “optionally substituted amino” or “optionallysubstituted carbamoyl” include optionally substituted lower alkyl (e.g.,methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g.,carbamoylmethyl), mono- or di-(lower)alkylcarbamoyl(lower)alkyl (e.g.,dimethylcarbamoylethyl), hydroxy(lower)alkyl, heterocyclyl(lower)alkyl(e.g., morpholinoethyl, tetrahydropyranylethyl),alkoxycarbonyl(lower)alkyl (e.g., ethoxycarbonylmethyl,ethoxycarbonylethyl), mono- or di-(lower)alkylamino(lower)alkyl (e.g.,dimethylaminoethyl)); (lower)alkoxy(lower)alkyl (e.g., methoxyethyl,ethoxymethyl, ethoxyethyl, isopropoxyethyl, and the like); acyl (e.g.,formyl, optionally substituted lower alkylcarbonyl (e.g., acetyl,propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl,octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl,alkoxycarbonylacetyl (e.g., ethoxycarbonylmethylcarbonyl),(lower)alkoxy(lower)alkylcarbonyl (e.g., methoxyethylcarbonyl),(lower)alkylcarbamoyl(lower)alkylcarbonyl (e.g.,methylcarbamoylethylcarbonyl), optionally substituted arylcarbonyl(e.g., benzoyl, toluoyl);

optionally substituted aralkyl (e.g., benzyl, 4-fluorobenzyl); hydroxy;optionally substituted lower alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, isopropylsulfonyl, 2,2,2-trifluoroethanesulfonyl,benzylsulfonyl, methoxyethylsulfonyl);arylsulfonyl optionally having a lower alkyl or halogen as a substituent(e.g., benzenesulfonyl, toluenesulfonyl, 4-fluorobenzenesulfonyl),cycloalkyl (e.g., cyclopropyl);aryl optionally having lower alkyl as a substituent (e.g., phenyl,tolyl);lower alkylaminosulfonyl (e.g., methylaminosulfonyl,dimethylaminosulfonyl);lower alkylaminocarbonyl (e.g., dimethylaminocarbonyl); loweralkoxycarbonyl (e.g., ethoxycarbonyl);cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclohexylcarbonyl);optionally substituted sulfamoyl (e.g., sulfamoyl, methylsulfamoyl,dimethylsulfamoyl);lower alkylcarbonylamino (e.g., methylcarbonylamino); heterocyclic group(e.g., morpholino, tetrahydropyranyl); optionally substituted amino(e.g., mono- or di-alkylamino (e.g., dimethylamino), formylamino), andthe like.

The above substituted amino or substituted carbamoyl may bemono-substituted or di-substituted.

“Lower alkenyl” refers to a linear or branched alkenyl having 2 to 8carbons and having one or more double bonds on said “lower alkyl”. Theexamples include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, and the like. Preferredis alkenyl having 2 to 6 carbons, more preferably 2 to 4 carbons.

With regard to “optionally substituted amino” or “optionally substitutedcarbamoyl”, two substituents of the amino group may be taken togetherwith the adjacent nitrogen atom to form a nitrogen-containingheterocycle which optionally includes a sulfur atom and/or an oxygenatom in the ring (preferably, the heterocycle is a 5- to 7-memberedring, and is preferably saturated). The heterocycle is optionallysubstituted with oxo or hydroxy. When a sulfur atom forms theheterocycle, said sulfur atom may be substituted with oxo. Examplesthereof include 5- or 6-membered rings such as piperazinyl, piperidino,morpholino, pyrrolidino, 2-oxopiperidino, 2-oxopyrrolidino,4-hydroxymorpholino, and the like.

Substituents of “optionally substituted lower alkyl” include at leastone group selected from Substituent Group alpha. The substitution may beof plurality and the substituents are same or different.

Substituents of “optionally substituted lower alkylene”, “optionallysubstituted lower alkenylene” and “optionally substituted loweralkynylene” include at least one group selected from Substituent Groupalpha. The substitution may be of plurality and the substituents aresame or different.

Substituents of “optionally substituted cycloalkyl” include at least onegroup selected from Substituent Group alpha. The substitution may be ofplurality and the substituents are same or different.

Substituents of “optionally substituted aryl” include at least one groupselected from Substituent Group alpha. The substitution may be ofplurality and the substituents are same or different.

Substituents of “optionally substituted heteroaryl” include at least onegroup selected from Substituent Group alpha.

The substitution may be of plurality and the substituents are same ordifferent.

Substituents of “optionally substituted aminosulfonyl” includesubstituted lower alkyl and at least one group selected from SubstituentGroup alpha.

Substituents of “optionally substituted lower alkyloxycarbonyl” includeat least one group selected from Substituent Group alpha.

Substituents of “substituted carbonyloxy” means “—O—C(═O)-substituent”,including optionally substituted lower alkyl, optionally substitutedlower alkenyl, optionally substituted lower alkynyl, an optionallysubstituted carbocyclic group, an optionally substituted heterocyclicgroup, amino optionally substituted with a heterocyclic group, and atleast one group selected from Substituent Group alpha.

Substituents of “optionally substituted carboxyl” include an optionallysubstituted lower alkyl, optionally substituted lower alkenyl,optionally substituted lower alkynyl, an optionally substitutedcarbocyclic group, and an optionally substituted heterocyclic group.

“Optionally substituted acyl group” includes carbonyl substituted withoptionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted lower alkynyl, an optionally substitutedcarbocyclic group, or an optionally substituted heterocyclic group.

Substituents of an “optionally substituted, saturated or unsaturated,monocyclic or fused cyclic quaternary ammonium group” include anoptionally substituted lower alkyl, one group selected from SubstituentGroup alpha, or any two substituents taken together may form acarbocyclic group or heterocyclic group. Lower alkylene, as asubstituent in a heterocyle containing a quanternary ammonium group, mayform a bridged structure between the quanternary ammonium group and anycarbon atom in the heterocyle.

“Substituent Group alpha” consists of halogen, hydroxy, lower alkoxy,lower alkylene, hydroxy(lower)alkoxy, (lower)alkoxy(lower)alkoxy,carboxy, amino, acylamino, lower(alkyl)amino, imino, hydroxyimino,lower(alkoxy)imino, lower(alkyl)thio, carbamoyl, lower(alkyl)carbamoyl,hydroxy(lower)alkylcarbamoyl, sulfamoyl, lower (alkyl) sulfamoyl,lower(alkyl)sulfinyl, cyano, nitro, a carbocyclic group, and aheterocyclic group.

The lower alkyl moiety in “lower alkoxy”, “hydroxy(lower)alkoxy”,“(lower)alkoxy(lower)alkoxy”, “lower(alkyl)amino”, “lower(alkoxy)imino”,“lower (alkyl)thio”, “lower (alkyl) carbamoyl”,“hydroxy(lower)alkylcarbamoyl”, and “lower (alkyl)sulfamoyl”,“lower(alkyl)sulfinyl”, “lower(alkyl)oxycarbonyl”, “lower(alkyl)sulfonyl”, is as defined as the above “lower alkyl”.

The lower alkenyl moiety in “lower(alkenyl)oxy”, is as defined as theabove “lower alkenyl”.

The aryl moiety in “aryloxy” is as defined as “aryl” mentioned below.

Preferred embodiments of substituents in “optionally substituted loweralkyl” include fluoro, chloro, bromo, hydroxy, carboxy, methoxy, ethoxy,hydroxymethoxy, hydroxyethoxy, methoxymethoxy, methoxyethoxy, amino,acetylamino, methylamino, dimethylamino, imino, hydroxyimino,methoxyimino, methylthio, carbamoyl, methylcarbamoyl,hydroxymethylcarbamoyl, sulfamoyl, methylsulfamoyl, loweralkylsulfamoyl, cyano, nitro, phenyl, cyclopropyl, cyclobutyl,cyclohexyl, pyridyl, morpholinyl, and the like.

Preferred embodiments of “optionally substituted lower alkyl” includemethyl, ethyl, isopropyl, tert-butyl, halo(lower)alkyl (e.g.,monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl,difluoromethyl, trifluoromethyl), carboxymethyl, carboxyethyl,carbamoylmethyl, carbamoylethyl, hydroxymethyl, hydroxyethyl,methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,methylthiomethyl, ethylthiomethyl, benzyl, phenethyl, 4-hydroxybenzyl,4-methoxybenzyl, 4-carboxybenzyl, and the like.

Preferred embodiments of substituents in “optionally substitutedcycloalkyl” include fluoro, chloro, bromo, hydroxy, carboxy, methoxy,ethoxy, hydroxymethoxy, hydroxyethoxy, methoxymethoxy, methoxyethoxy,amino, acetylamino, methylamino, dimethylamino, imino, hydroxyimino,methoxyimino, methylthio, carbamoyl, methylcarbamoyl,hydroxymethylcarbamoyl, sulfamoyl, methylsulfamoyl, loweralkylsulfamoyl, cyano, nitro, phenyl, cyclopropyl, cyclobutyl,cyclohexyl, pyridyl, morpholinyl, and the like.

“Carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl andnon-aromatic fused carbocyclic groups, and the like.

“Cycloalkyl” has 3-10 carbons, preferably 3-8 carbons, and morepreferably 3-6 carbons, and includes, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, and the like.

“Cycloalkenyl” is cycloalkyl which contains at least one double bond atany position(s), and includes, for example, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, andcyclohexadienyl, and the like.

“Aryl” includes phenyl, naphthyl, anthryl, phenanthryl, and the like,and phenyl is preferable.

“Aromatic carbocycle” means a ring derived from aryl as described below.

“Aromatic heterocycle” means an aromatic ring, which is monocyclic orbicyclic or more, having same or different one or more hetero atomselected independently from O, S or N.

The aromatic heterocyclic group which is bicyclic or more includes thosewherein a monocyclic or bicyclic or more aromatic heterocyle iscondensed with “aromatic carbocyle” described above.

“Non-aromatic carbocyclic group” includes the above “cycloalkyl” and“cycloalkenyl”, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl,cyclooctynyl, and cyclohexadienyl and the like.

“Non-aromatic fused carbocyclic group” includes a group in which one ormore cyclic group selected from said “cycloalkyl” and “cycloalkenyl” isfused to said “cycloalkyl” “cycloalkenyl” or “aryl”, and includes, forexample, indanyl, indenyl, tetrahydronaphthyl, and fluorenyl, and thelike.

“Heterocyclic group” includes heterocyclic groups having at least onehetero atom arbitrarily selected from O, S, and N in the ring, andincludes, for example, 5- or 6-membered monocyclic non-aromaticheterocyclic group such as pyrrolidyl, piperidinyl, piperadinyl,morpholinyl, tetrahydrofuranyl, tetrohydrothienyl, and the like; 5- or6-membered monocyclic heteroaryl such as pyrrolyl, imidazolyl,pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl,triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl,thiazolyl, thiadiazolyl, furyl, thienyl, and the like; 9- or 10-memberedbicyclic fused heterocyclic groups such as indolyl, isoindolyl,indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl,purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl,benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,benzothienyl, benzotriazolyl, imidazopyridyl, pyrazolopyridine,triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl,quinolyl, isoquinolyl, naphthyridinyl, dihydrobenzofuryl,tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazine,tetrahydrobenzothienyl, and the like; tricyclic fused heterocyclicgroups such as carbazolyl, acridinyl, xanthenyl, phenothiadinyl,phenoxathiinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, and thelike; non-aromatic heterocyclic groups such as dioxanyl, thiiranyl,oxiranyl, oxathiolanyl, azetidinyl, thianyl, thiazolidine, pyrrolidinyl,pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholino,dihydropyridyl, dihyrobenzimidazolyl, tetrahydropyridyl,tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl,tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl,tetrahydrodiazepinyl, and the like. Preferably, the heterocyclic groupis a 5- or 6-membered monocyclic heterocyclic group or 9- or 10-memberedbicyclic fused heterocyclic group, and more preferably, a 5- or6-membered heteroaryl or 9- or 10-membered bicyclic fused heterocyclicgroup.

“Heteroaryl” means an aromatic heterocyclic group described above.Preferred is 5- or 6-membered monocyclic heteroaryl or 9- or 10-memberedbicyclic heteroaryl.

“Heterocycle” means a ring derived from a heterocyclic group asdescribed above. Preferred is 5- or 6-membered monocyclic heterocycle or9- or 10-membered bicyclic heterocycle.

“Fused heterocycle” means a ring condensed with at least oneheterocycle, includes those wherein monocyclic, bicyclic or moreheterocyle is condensed with “carbocyle” described above.

Preferred is 9- or 10-membered bicyclic heterocycle having at least onenitrogen atom.

“Monocyclic heterocycle” is preferably 5- to 7-membered heterocycle, andmore preferably 6-membered heterocycle having at least one nitrogenatom.

“Non-aromatic heterocyclic group” means a group which does not showaromatic character of the “heterocyclic group”.

Substituents of “optionally substituted carbocyclic group” “optionallysubstituted heterocyclic group”, “optionally substituted non-aromaticcarbocyclic group”, and “optionally substituted non-aromaticheterocyclic group” include optionally substituted lower alkyl, and atleast one group selected from Substituent Group alpha.

Preferred embodiments of substituents in “optionally substitutedcarbocyclic group”, “optionally substituted heterocyclic group”,“optionally substituted non-aromatic carbocyclic group” and “optionallysubstituted non-aromatic heterocyclic group” include methyl, ethyl,isopropyl, tert-butyl, a fluorine atom, a chlorine atom, a bromine atom,hydroxy, carboxy, methoxy, ethoxy, hydroxymethoxy, hydroxyethoxy,methoxymethoxy, methoxyethoxy, amino, acetylamino, methylamino,dimethylamino, imino, hydroxyimino, methoxyimino, methylthio, carbamoyl,methylcarbamoyl, hydroxymethylcarbamoyl, sulfamoyl, methylsulfamoyl,lower alkylsulfamoyl, cyano, nitro, phenyl, cyclopropyl, cyclobutyl,cyclohexyl, pyridyl, morpholinyl, and the like.

“5- or 6-membered aromatic heterocyclic group having 1-3 nitrogen atoms”includes pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, triazinyl, isoxazolyl, oxazolyl,oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, andthe like.

Examples of “optionally substituted carbocyclic group” or “optionallysubstituted heterocyclic group” of R1 include phenyl, aminothiazole,aminothiadiazole, thiophene, furan, benzothiazole, pyridine, pyrimidine,pyridazine, aminopyridine, and the like, each optionally substitutedwith hydroxyl and/or halogen. Preferred Examples include the followings:

Examples of R^(2A) include hydrogen, optionally substituted amino,—COOH, —SO₃H, optionally substituted aminosulfonyl, carboxyl, optionallysubstituted carbamoyl, hydroxyl, substituted carbonyloxy, and the like.

In Preferred examples of

R^(2B) is hydrogen and R^(2A) is the following group:1) substituted amino group shown below:

2) substituted aminosulfonyl group shown below:

wherein ring B represents an optionally substituted heterocyclic group;3) substituted carbamoyl group shown below:

wherein ring B represents an optionally substituted heterocyclic group;or4) substituted carbonyloxy shown below:

wherein ring B represents an optionally substituted.

Alternatively, R^(2A) and R^(2B) may be taken together to form asubstituted methylidene group shown below:

wherein R⁹ is optionally substituted lower alkyl, preferably

Also, R^(2A) and R^(2B) may be taken together to form optionallysubstituted hydroxyimino shown below:

wherein R⁹ is as defined above. Preferred is group shown below.

wherein each symbol is as defined above.

Examples of “R⁷ and R⁸” includes hydrogen, fluoro, chloro, hydroxy,carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl,difluoromethyl, trifluoromethyl, carboxymethyl, carboxyethyl,carbamoylmethyl, carbamoylethyl, hydroxymethyl, hydroxyethyl,methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,methylthiomethyl, ethylthiomethyl, benzyl, 4-hydroxybenzyl,4-methoxybenzyl, 4-carboxybenzyl, 3,4-dihydroxybenzyl, phenyl,4-hydroxyphenyl, 3,4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl,isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl,thiadiazolyl, furyl, thienyl, and the like.

Preferred combinations of (R⁷, R⁸) include (hydrogen, hydrogen),(methyl, hydrogen), (hydrogen, methyl), (methyl, methyl), (ethyl,hydrogen), (hydrogen, ethyl), (ethyl, ethyl), (phenyl, hydrogen),(hydrogen, phenyl), (dihydroxyphenyl, hydrogen), (hydrogen,dihydroxyphenyl), (carboxymethyl, hydrogen), (hydrogen, carboxymethyl),(carboxyethyl, hydrogen), (hydrogen, carboxyethyl), (hydroxyethyl,hydrogen), (hydrogen, hydroxylethyl), (carbamoylmethyl, hydrogen),(hydrogen, carbamoylmethyl), (trifluoromethyl, hydrogen), (carboxy,hydrogen), (carbamoylethyl, hydrogen), (benzyl, hydrogen),(dihydroxybenzyl, hydrogen), and the like. More preferred combinationsof (R⁷, R⁸) include, (methyl, methyl), (hydrogen, carboxymethyl), and(carboxyethyl, hydrogen).

Preferred examples of the above substituted hydroxyimino include groupsshown bellow.

More preferred examples of the above substituted hydroxyimino includegroups shown bellow.

In the case where “R⁷ and R⁸ may be taken together with a neighboringatom to form an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group” in the formula:

wherein each symbol is as defined,

R⁷ and R⁸ may form cycloalkane, cycloalkene, or a non-aromaticheterocycle optionally substituted with a group selected fromSubstituent Group alpha. For example, a group of the formula:

includes those shown below:

wherein each ring is optionally substituted with a group selected fromSubstituent Group alpha.

Examples of “Q” include a single bond, phenyl, pyridyl, and the like. Asingle bond is particularly preferable.

“m” is preferably 0 or 1, and 0 is particularly preferable.

Preferred examples of the above embodiments include:

“R³” is preferably hydrogen or —OCH₃, and more preferably hydrogen.

Lower alkyl of R5^(A) and R5^(B) includes linear or branched alkylhaving 1-6 carbons, preferably 1-4 carbons, for example, methyl, ethyl,n-propyl, isopropyl, n-buthyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, and the like.

Examples of combinations of (R^(5A), R^(5B)) include (hydrogen, methyl),(hydrogen, ethyl), (hydrogen, isopropyl), (hydrogen, tert-butyl),(methyl, methyl), and the like. Preferably, (R^(5A), R^(5B)) is(hydrogen, methyl) or (methyl, methyl).

Carbocycle of “R5^(A) and R5^(B) may be taken together with theneighboring atom to form optionally substituted carbocycle” includecycloalkane and cycloalkene which have 3-8 carbons, preferably 3-6carbons. Preferred embodiments include cyclopropane, cyclobutane,cyclopentane, cyclopentene, cyclohexcane, cyclohexcene, and the like,more preferably include cyclopropane. Substituents of the carbocycleinclude halogen, hydroxyl, lower alkyl, lower alkoxy, and the like.Preferred embodiments include fluoro, chloro, hydroxyl, methyl, ethyl,isopropyl, tert-buthyl, methoxy, ethoxy, isopropoxy, and the like.

Heterocycle of “R5^(A) and R5^(B) may be taken together with theneighboring atom to form optionally substituted heterocycle” include anaromatic or non-aromatic, monocyclic or fused cyclic ring. Preferredembodiments include non-aromatic 3- to 6-membered monocyclic ring.Substituents of the heterocycle include halogen, hydroxyl, lower alkyl,lower alkoxy, and the like. Preferred embodiments include fluoro,chloro, hydroxyl, methyl, ethyl, isopropyl, tert-buthyl, methoxy,ethoxy, isopropoxy, and the like.

Optionally substituted methylidene of “R5^(A) and R5^(B) may be takentogether to form optionally substituted methylidene” is shown by theformula;

wherein, R¹³ and R¹⁴ are each independently hydrogen, halogen, oroptionally substituted lower alkyl, and preferred R¹³ and R¹⁴ arehydrogen.

“L” is —CH₂—, —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —S—, —CH₂—S—, —CH═CH—S—or —CH═CH—CH₂—S—, preferably —CH₂—, —CH₂—CH═CH—, —S— or —CH₂—S—.

E is an optionally substituted, saturated or unsaturated, monocyclic orfused cyclic group having at least one quaternary ammonium ion and ispreferably selected from the above formulae (1) to (77) which areoptionally substituted on the ring. The substituents on the ring includean optionally substituted lower alkyl or one or more group selected fromsubstituent Group alpha. Preferred embodiments of such substitutentinclude methyl, ethyl, isopropyl, tert-butyl, fluorine atom, chlorineatom, bromine atom, hydroxyl, carboxyl, methoxy, ethoxy, hydroxymethoxy,hydroxyethoxy, methoxymethoxy, methoxyethoxy, methylene, ethylene,propylene, butylene, amino, acetylamino, methylamino, dimethylamino,imino, hydroxyimino, methoxyimino, methylthio, carbamoyl,methylcarbamoyl, hydroxymethylcarbamoyl, sulfamoyl, methylsulfamoyl,(lower)alkylsulfamoyl, cyano, nitro, phenyl, cyclopropyl, cyclobutyl,cyclohexyl, pyridyl, morpholinyl, and the like. More preferredembodiments include a ring unsubstituted or mono- or di-substituted witha hydroxyl group. Such ring mono- or di-substituted with a hydroxylgroup may be substituted additionally with another substituent. Herein,when a substitutent is lower alkylene such as ethylene, propylene, orbutylene, the lower alkylene may form a bridged structure between thequanternary ammonium group and any carbon atom or between any two carbonatoms in E.

Preferred embodiment of E is the formula (I-D):

wherein,

the dashed line is a bond in the ring;

the bond to the cationic nitrogen atom binds to L, and the other bondbinds to R¹⁰;

provided,

when a cationic nitrogen atom binds to R¹⁰, the dashed line is absent,and

when a cationic nitrogen atom does not bind to R¹⁰, the dashed line is asingle bond between the cationic nitrogen atom and a neighboring atom oran alkylene group between the cationic nitrogen atom and a ring memberatom other than said neighboring atom,

or the formula (I-E):

wherein, the bond to the cationic nitrogen atom binds to L, and theother bond binds to R¹⁰; R^(x) is optionally substituted lower alkyl.

When L is —S—, —CH₂—S—, —CH═CH—S— or —CH═CH—CH₂—S—, preferred embodimentof E is a monocyclic or fused heterocyclic group represented by theformula (I-D′):

wherein,

the bond to the cationic nitrogen atom binds to R¹⁰, and the other bondbinds to L,

more preferred E is an optionally substituted pyridinium group or anoptionally substituted fused pyridinium group.

Preferred examples of E include the following formulae optionallysubstituted on the ring:

wherein one bond to the quaternary nitrogen atom binds to L, and theother bond binds to R¹⁰; p is an integer from 1 to 3; n is 1 or 2; eachRx is independently an optionally substituted lower alkyl group.

Among the above formulae, a group selected from the group consisting ofthe formulae (1) to (7), (10) to (12), (14), (25) to (29), (31), (41) to(44), (47), (50), (52), (53), (59), (60), (64), (73) and (77) is morepreferable.

Particularly, a group selected from the group consisting of the formulae(2), (3), (5), (6), (7), (10), (11), (26), (27), (41), (42), (59), (60)and (77) is preferable.

In the subject invention, E is an optionally substituted, saturated orunsaturated, monocyclic or fused cyclic group having at least onequaternary ammonium ion and includes the following embodiment:

1) E is an aromatic heterocyclic group wherein two hydroxyl groups eachbinds to each of two adjacent carbon atoms on the aromatic ring;

2) E is a heterocyclic group wherein a hydroxyl group(s) do not attachedto the ring, or when a hydroxyl group(s) attached, two hydroxyl groupeach do not bind to each of two adjacent carbon atoms on the ring; and

3) E is a non-cyclic group.

Preferred is 1) or 2).

Preferable examples of the above 1) include:

wherein one bond to the quaternary nitrogen atom binds to L, and theother bond binds to R¹⁰.

Preferred examples of E-R¹⁰ include:

wherein one bond to the quaternary nitrogen atom binds to L, and R¹² isas defined above.

More preferred examples of E-R¹⁰ include:

wherein the bond to the quaternary nitrogen atom binds to L.

R⁶ is hydrogen or optionally substituted lower alkyl, preferablyhydrogen, linear or branched alkyl having 1-4 carbons or linear orbranched alkyl having 1-4 carbons substituted with carboxy, halogen,hydroxyl or carbonyl, more preferably hydrogen, methyl, ethyl,tert-buthyl,

In accordance with the present invention, variable terms “B” or “D”,respectively. are as defined throughout the specification and as below,i.e.:

B is non-existent, a single bond or a 5- or 6-membered heterocyclicgroup containing at least 1-3 nitrogen atoms.

D is non-existent, a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —NR⁶—,—NR⁶—C(═O)—, —C(═O)—NR⁶—, —C(═O)—C(═O)—, —NR⁶—C(═O)—NR⁶—,—C(═O)—C(═O)—NR⁶—, —C(═O)—NR⁶—C(═)—, —NR⁶—C(═O)—C(═O)—, —NR⁶—NR⁶—C(═O)—,—C(═O)—NR—NR⁶—, —N═N—C(═O)—, —C(═O)—N═N—, —C═N—NR⁶—C(═O)—, —C═N—C(═O)—,—N═C—C(═O)—, —C═N—C(═O)—NR⁶—, —NR⁶—C(═O)—C(═N—OR⁶)—,—C(═N—OR⁶)—C(═O)—NR⁶—, —NR⁶—C(═N—OR⁶)—, —C(═N—OR⁶)—NR⁶—,—C(═O)—C(═N—OR⁶)—, —C(═N—OR⁶)—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—NR⁶—,—NR⁶—S(═O)₂—, —NR⁶—CH₂—, —CH₂—NR⁶— or —S(═O)₂—.

In light of the above definitions and throughout the specification, theterms “B” and “D” may respectively or individually be non-existent, orif both “B” and “D” represent single bonds, then “B” and “D” may betaken together or collectively (i.e., “B-D” joined together) such thatit may represent one single bond attached to corresponding adjacent oradjoining functional groups as defined by the present invention.

Preferred embodiments of R¹⁰ as a group represented by the formula:

are provided below.

G is preferably a single bond or optionally substituted lower alkylene,and more preferably a single bond, methylene or ethylene.

B is non-existent, preferably a single bond or a group represented bythe formula:

wherein the bond of the left side is attached to G and the bond of theright side is attached to D.

B is more preferably a single bond.

-   -   D is preferably a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—,        —NR6-, —O—, —C(═O)—C(═O)—, —NR6-C(═O)—NR6-, —C(═O)—C(═O)—NR6-,        —C(═O)—NR6-C(═O)—, —NR6-C(═O)—C(═O)—, —NR6-C(═O)—, —C(═O)—NR6-,        —NR6-NR6-C(═O)—, —C(═O)—NR6-NR6-, —N═N—C(═O)—, —C(═O)—N═N—,        —C═N—NR6-C(═O)—, —C═N—C(═O)—, —N═C—C(═O)—, —C═N—C(═O)—NR⁶—,        —NR⁶—C(═O)—C(═N—OR6)-, —C(═N—OR6)-C(═O)—NR6-, —NR6-C(═N—OR6)-,        —C(═O)—C(═N—OR6)-, —C(═N—OR6)-C(═O)— or —C(═N—OR6)-NR⁶—, wherein        R⁶ is hydrogen, methyl, carboxymethyl or 2-carboxypropane-2-yl,        and more preferably a single bond, —C(═O)—, —C(═O)—C(═O)—,        —NH—C(═O)—C(═O)—, —NH—C(═O)—, —NH—C(═O)—C(═N—OR⁶)—,        —C(═O)—C(═N—OR⁶)—, —NH—, —O—, or —C═N—NH—C(═O)—, R⁶ is hydrogen,        methyl, ethyl, tert-buthyl, carboxymethyl, 2-carboxypropan-2-yl        or 1-carboxyethyl.

Preferred combinations of “-G-B-D-” include the formulae as shown below:

wherein,k is an integer of to 3, R6 is as defined above,the wavy line means that the bond is in cis or trans configuration, or amixture thereof.

Preferable examples of “-E-G-B-D-” include the formulae as shown below:

wherein,Me represents a methyl group,h is an integer 0 to 3,R⁶ is hydrogen, methyl, ethyl, tert-buthyl, carboxymethyl,2-carboxypropan-2-yl or 1-carboxyethyl,the wavy line means that the bond is in cis or trans configuration, or amixture thereof.

In one aspect of the present invention with regard to Formula (I-B):

where:

ring A is defined as a fused heterocycle ring system comprised of atleast two (2) rings fused together;

where:

R⁴ optionally is substituted on each of the at least two (2) rings ofthe fused heterocycle ring system defined as ring A, such that each R4substituent on each ring of the fused heterocycle ring systemindependently are selected from identical or different substituents;

where:

-   -   each R⁴ as defined above optionally is substituted independently        on each ring of the fused heterocycle ring is selected from        hydrogen, halogen, oxo, —OH, —CN, —NO₂, —O—C(═O)—R⁹, —C(═O)—R⁹,        —C(═O)—OH, —C(═O)—OR⁹, —OR^(9′), —NR⁹R⁹, —SO₂R⁹, —SR⁹,        —NR⁹—C(═O)—R⁹, optionally substituted lower alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, or        optionally substituted heteroaryl;        -   provided that two hydroxyl groups on ring A bind            respectively to carbon atoms each adjacently locates; and n            is an integer from 0 to 2.

Preferred embodiments of a group of the formula:

wherein:

A is a benzene ring, monocyclic heterocycle or fused heterocycle,respectively as defined throughout the specification;

each R⁴ is independently hydrogen, halogen, oxo, —OH, —CN, —NO2,—O—C(═O)—R⁹, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR⁹, —NR⁹R⁹, —SO₂R⁹,—SR⁹, —NR⁹—C(═O)—R⁹, lower alkyl, halo(lower)alkyl, cycloalkyl, aryl, orheteroaryl; each R⁹ is independently lower alkyl or halo(lower)alkyl; nis an integer from 0 to 2; provided that two hydroxyl groups on the ringA bind respectively to carbon atoms each adjacently locates.

Preferred examples of ring A include benzene, a 5- to 7-memberedmonocyclic heterocycle and a 8- to 12-membered fused heterocycle and asdefined throughout the instant specification.

Preferred examples of 5- to 7-membered monocyclic heterocycle of ring Ainclude the ring having 1 to 3 nitrogen atom(s), more preferably onenitrogen atom.

Preferred examples of 8- to 12-membered fused heterocycle of ring Ainclude the ring having 1 to 4 nitrogen atom(s), more preferably one ortwo nitrogen atom(s).

More preferred examples of ring A include benzene, a 5- to 6-memberedmonocyclic heterocycle having one nitrogen atom and a 9- to 10-memberedfused heterocycle having one or two nitrogen atom(s).

Preferred examples of a group of the formula:

include the formulae as shown below:

wherein,each R^(4a), R^(4b) R^(4c) and R^(4d) is independently hydrogen,halogen, —OH, —CN, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR⁹, optionallysubstituted lower alkyl, or optionally substituted cycloalkyl;R⁹ is independently lower alkyl or halo(lower)alkyl;R⁶ is hydrogen, or optionally substituted lower alkyl.

More preferred examples of a group of the formula:

include the formulae as shown below:

Wherein, Me represents a methyl group.

Preferred examples of a group of the formula (1-C-1):

include the formulae as shown below:

wherein,each R^(4a), R^(4b) R^(4c) and R^(4d) is independently hydrogen,halogen, —OH, —CN, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR⁹, optionallysubstituted lower alkyl, or optionally substituted cycloalkyl;R⁹ is independently lower alkyl or halo(lower)alkyl;R⁶ is hydrogen, or optionally substituted lower alkyl;the wavy line means that the bond is in cis or trans configuration, or amixture thereof.

Examples of R^(4a), R^(4b) R^(4c) and R^(4d) include hydrogen, chloro,fluoro, bromo, cyano, hydroxy, carboxy, acetyl, methoxy, ethoxy,trifluoromethyl, and the like. Preferably, each R^(4a), R^(4b) R^(4c)and R^(4d) is independently hydrogen, hydroxy, carboxy, methoxy, fluoro,trifluoromethyl, or chloro.

More preferred examples of a group of the formula (1-C-1):

include the formulae as shown below:

wherein, R⁶ is hydrogen, methyl, ethyl, tert-buthyl, carboxymethyl,2-carboxypropan-2-yl or 1-carboxyethyl, the wavy line means that thebond is in cis or trans configuration, or a mixture thereof.

The nomenclature of the substitution position on the cephem skeleton ofFormula (I) is as follows. As used herein, 3-side chain, 4-side chainand 7-side chain respectively refer to groups binding to the 3-position,4-position and the 7-position of the cephem skeleton

Esters of Formula (I) preferably include those at the 7-side chain.Esters at the carboxyl group on the 7-side chain include compounds,wherein any carboxyl group of optionally substituted amino, optionallysubstituted aminosulfonyl, carboxyl, optionally substituted(lower)alkyloxycarbonyl, optionally substituted carbamoyl, substitutedcarbonyloxy, or the like at the terminal of R¹, R^(2A) or R^(2B) shownin the formula:

wherein each symbol is as defined above, is esterified. For example, inthe case of carboxyl (—COOH), such esters are represented by thestructural formula —COOR^(a), wherein R^(a) is an ester residue such asa carboxyl-protecting group or the like. Such esters include thoseeasily metabolized in the body to form a carboxylic state.

The aforementioned protecting groups for carboxyl or the like may be anygroup as long as it can be protected and/or deprotected by a methoddescribed in Protective Groups in Organic Synthesis, written by T. W.Greene, John Wiley & Sons Inc. (1991), or the like. Examples thereofinclude lower alkyl (e.g., methyl, ethyl, t-butyl),(lower)alkylcarbonyloxymethyl (e.g., pivaloyl), optionally substitutedaralkyl (e.g., benzyl, benzhydryl, phenethyl, p-methoxybenzyl,p-nitrobenzyl), silyl groups (t-butyldimethylsilyl,diphenyl(t-butyl)silyl), and the like.

Amino-protected compounds at the amino on the 7-side chain of Formula(I) refer to the structures in which the amino on the ring (e.g.,thiazole, thiadiazole) has been protected.

The amino protected group is represented by the formula —NHR^(c) whereinR^(c) represents an amino-protecting group. Such amino-protecting groupsinclude those groups that are readily metabolized in the body to formamino. The aforementioned amino-protecting groups may be any group aslong as it can be protected and/or deprotected by a method described inProtective Groups in Organic Synthesis, written by T. W. Greene, JohnWiley & Sons Inc. (1991), or the like. Examples thereof include(lower)alkoxycarbonyl (e.g., t-butoxycarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl), optionally substituted aralkanoyl (e.g.,benzoyl, p-nitrobenzoyl), acyl (e.g., formyl, chloroacetyl), and thelike.

The Compound (I) of the subject invention is not limited to particularisomers, but includes any possible isomers (e.g., keto-enol isomer,imine-enamine isomer, diastereoisomer, geometrical isomer, opticalisomer, rotamer, etc.), racemates and a mixture thereof.

For example, the Formula (I):

includes

For example, the formula:

wherein each symbol is as defined above, includes the followingresonance structures:

wherein R⁴ is as defined above.

Also, the group “E” in Formula (I), for example, includes the followingresonance structures:

wherein each symbol is as defined above.

For example, the formula:

wherein, R6 is as defined above;includes

and a mixture thereof.

At least one hydrogen atom, carbon atom and/or another atom may bereplaced with an isotope of said hydrogen atom, carbon atom and/oranother atom. Examples of such isotope include hydrogen, carbon,nitrogen, oxygen, sulfur, fluorine, iodine and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³I and ³⁶Cl. Thecompound of Formula (I) include compounds having an atom replaced withsuch isotope. Such compound replaced with an isotope are useful as apharmaceutical product, and such compound include all of radiolabeledcompound of Formula (I). Also, the subject invention includes any methodof radioactive labeling for the production of such radiolabeledcompound, and thus, it is useful in a research for metabolicpharmacokinetics, binding assay and/or as a diagnostic tool.

A radiolabeled compound of Formula (I) may be prepared according to thetechnique well known in the art. For example, tritium can be introducedinto a specific compound of Formula (I) by catalytic dehalogenationusing tritium to prepare a tritium-labeled compound of Formula (I). Thismethod comprises reaction of a precursor which is a compound of Formula(I) appropriately halogenated with tritium gas in the presence ofappropriate catalyst, such as Pd/C, in the presence or absence of abase. For another method for the preparation of a tritium-labeledcompound, see the literature, Isotopes in the Physical and BiomedicalSciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).¹⁴C-labeled compound can be prepared using a starting material having¹⁴C.

Salts of a compound of Formula (I) include those formed with aninorganic or organic acid by a carboxyl group in the 7-side chain and/oran amino group in the 7-side chain; and those formed with a counteranion by a quaternary amine moiety in the 3-side chain.

Pharmaceutically acceptable salts of a compound of Formula (I) include,for example, salts formed with alkali metal (e.g. lithium, sodium,potassium, etc.), alkaline earth metal (e.g. calcium, barium, etc.),magnesium, transition metal (e.g. zinc, ferrum, etc.), ammonia, organicbase (e.g. trimethylamine, triethylamine, dicyclohexylamine,ethanolamine, diethanolamine, triethanolamine, meglumine,diethanolamine, ethylenediamine, pyrydine, picoline, quinoline, etc.)and amino acid, or salts formed with inorganic acid (e.g. hydrochloricacid, sulphuric acid, nitric acid, carbonic acid, hydrobromic acid,phosphoric acid, hydroiodic acid, etc.), and organic acid (e.g. formicacid, acetic acid, propionic acid, trifluoroacetic acid, citric acid,lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid,mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid,ascorbic acid, benzenesulphonic acid, p-toluenesulfonic acid,methanesulphonic acid, ethanesulphonic acid, etc, particularly, saltsformed with hydrochloric acid, sulphuric acid, phosphoric acid, tartaricacid, methanesulphonic acid. These salts can be formed according to theconventional method.

The compound of Formula (I) or pharmaceutically acceptable salts thereofmay form a solvate (e.g., hydrate) and/or a crystalline polymorphism,and the subject invention also includes such solvates and crystallinepolymorphisms. In such “solvate”, any number of solvent molecules (e.g.,water molecule, etc.) may be coordinated to the compound of Formula (I).By leaving the compound of Formula (I) or pharmaceutically acceptablesalt thereof in the atmosphere, it may absorb moisture to adhere withabsorbed water or form a hydrate thereof. Also, a crystallinepolymorphism of the compound of Formula (I) or pharmaceuticallyacceptable salt thereof can be formed by recrystallization.

The compound of Formula (I) or pharmaceutically acceptable salt thereofmay form a prodrug, and the subject invention includes such prodrugs.Prodrug is a derivative of the compound of the invention having a groupchemically- or metabolically-degradable to be transformed into apharamacologically active compound by solvolysis or under physiologicalcondition in vivo. Prodrug includes compounds which can be transformedinto the compound of Formula (I) by enzymatically oxidization, reductionor hydrolysis under physiological condition in vivo, or transformed intothe compound of Formula (I) by hydrolysis with gastric acid, etc.Methods for selection and production of appropriate prodrug derivativecan be found, for example, in Design of Prodrugs, Elsevier, Amsterdam1985.

Prodrug may be active compound in itself.

When the compound of Formula (I) or pharmaceutically acceptable saltthereof has hydroxyl, acyloxy derivatives or sulfonyloxy derivatives canbe prepared as a prodrug. For example, such compound having hydroxyl maybe reacted with an appropriate acyl halide, acid anhydrate or anappropriate sulfonyl chloride, sulfonyl anhydrate, mixed anhydrate,etc., or may be reacted using a coupling agent, such as for examples,those having CH₃COO—, C₂H₅COO—, t-BuCOO—, C₁₅H₃₁COO—, PhCOO—,(m-NaOOCPh)COO—, NaOOCCH₂CH₂COO—, CH₃CH(NH₂)COO—, CH₂N (CH₃)₂COO—,CH₃SO₃—, CH₃CH₂SO₃—, CF₃SO₃—, CH₂FSO₃—, CF₃CH₂SO₃—, p-CH₃—O-PhSO₃—,PhSO₃—, p-CH₃PhSO₃—.

For the synthesis of a compound of Formula (I), A compound of theformula (I-H):

wherein,

Y is a leaving group; P² is a protecting group;

R^(5A), R^(5B) and L are as defined above,

or a pharmaceutically acceptable salt thereof is preferred as anintermediate.

The compound of the formula (I-H), or a salt thereof, wherein P² isbenzhydryl group, p-methoxybenzyl group, trityl group,2,6-dimethoxybenzyl group, methoxymethyl group, benzyloxymethyl group or2-(trimethylsilyl)ethoxymethyl group is preferred as an intermediate.

The compound of the formula (I-H), or a salt thereof, wherein R5^(A) ismethyl and R5^(B) is hydrogen is preferred as an intermediate.

For the synthesis of a compound of Formula (I), a compound of theformula (I-I):

or a salt thereof,wherein,

Y is a leaving group; P² is a protecting group;

R5^(A) and L are as defined above,

or a pharmaceutically acceptable salt thereof is preferred as anintermediate.

For the synthesis of a compound of Formula (I), a compound of theformula:

wherein, Y is a leaving group; P2 is a protecting group; R5A, R5B and Lare as defined above,or a pharmaceutically acceptable salt thereof is preferred as anintermediate. The 7-amino can be formed with a counter anion (Z⁻) to bea salt (—NH₃+Z⁻)

The leaving group includes halogen (Cl, Br, I, F), acetoxy,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy,etc.

Preferred example of a compound of the formula:

wherein, Y is a leaving group; P2 is a protecting group; R5A, R5B and Lare as defined above,is a compound of the formula:

wherein, Y is a leaving group; P2 is a protecting group; L is as definedabove.

As described in the following General Synthesis and Examples, anintermediate compound described above is reacted with side chainmoieties at the 3-, 4- and 7-positions of the cephem skeleton to obtaina compound of Formula (I). Examples of the protecting group “P²” includethose described in the following General Synthesis, and preferably,benzhydryl, p-methoxybenzyl, trityl, 2,6-dimethoxybenzyl, methoxymethyl,benzyloxymethyl or 2-(trimethylsilyl)ethoxymethyl, etc.

(General Synthesis Method)

Scheme 1 represents a general scheme for the preparation of compounds ofthe present invention.

wherein, P¹ and P² are protecting groups; Y is a leaving group (e.g., ahalogen (Cl, Br, I, F), methanesulfonyloxy, pe-toluenesulfoxy); R5 ishydrogen or lower alkyl; other symbols are as defined above.

1) Formation of 2-Methyl Cephem: Synthesis of Compound (X) Step 1

The 4-carboxyl group of the compound (II) is protected with acarboxyl-protecting group by a conventional method to give the compound(III). The carboxyl-protecting group is exemplified by diphenyl methyl,p-methoxybenzyl etc.

The reaction solvents include, for example, ethers (e.g., dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether), esters (e.g., ethyl formate, ethyl acetate, isopropyl acetate),halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbontetarachloride), hydrocarbons (e.g., n-hexane, benzene, toluene), amides(e.g., formamide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone), ketones (e.g., acetone, methyl ethyl ketone),nitriles (e.g., MeCN, propionitrile), dimethylsulfoxide, water and amixed solvent thereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −80° C. to 80° C., more preferablyfrom about −60° C. to 60° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

Step 2

The compound (IV) is obtained by subjecting the compound (III) tooxidation reaction using an oxidation agent well-known to those skilledin the art (e.g., m-chloroperbenzoic acid, acetic peroxide).

The reaction solvents include, for example, ethers (e.g., anisole,dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether,diisopropyl ether), esters (e.g., ethyl formate, ethyl acetate, n-butylacetate, isopropyl acetate), halogenated hydrocarbons (e.g.,dichloromethane, chloroform, carbon tetarachloride), hydrocarbons (e.g.,n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., MeCN,propionitrile), nitros (e.g., nitromethane, nitorethane, nitrobenzene),dimethylsulfoxide, water, and a mixed solvent selected from two or moreof these solvents. The reaction temperature is usually in the range offrom about −100° C. to 100° C., preferably from about −80° C. to 50° C.,more preferably about −60° C. to −30° C. The reaction time may varyaccording to the reagents, solvents or reaction temperature to beemployed, but usually is carried out for 0.5 to 24 hours.

Step 3

The compound (IV) is reacted with aldehyde (i.e. R⁵CHO) and a primary orsecondary amine to give the compound (V).

Aldehyde include, for example, formaldehyde and lower alkyl aldehyde(e.g. acetaldehyde, propionaldehyde). Aldehyde is generally used in anamount of about 1 to 100 moles, preferably 1 to 30 moles, for 1 mole ofthe compound (IV).

A primary or secondary amine include, for example, methylamine,dimethylamine, ethylamine and diethylamine. A primary or secondaryamine, including its salt, is generally used in an amount of about 1 to100 moles, preferably 1 to 30 moles, for 1 mole of the compound (IV).

The reaction solvents include, for example, ethers (e.g., dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether), esters (e.g., ethyl formate, ethyl acetate, isopropyl acetate),halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbontetarachloride), hydrocarbons (e.g., n-hexane, benzene, toluene), amides(e.g., formamide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone), ketones (e.g., acetone, methyl ethyl ketone),nitriles (e.g., MeCN, propionitrile), dimethylsulfoxide, water, and amixed solvent thereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −80° C. to 80° C., more preferablyfrom about 0° C. to 80° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

Step 4

The compound (V) is reacted with a reductant (e.g., zinc, copper,mixture thereof) and an acid (e.g., Hydrochloric acid, acetic acid,formic acid) to give the compound (VI).

Zinc is generally used in an amount of about 1 to 100 moles, preferably1 to 30 moles, for 1 mole of the compound (V). Acid (e.g., Hydrochloricacid, acetic acid, formic acid) is generally used in an amount of about1 to 100 moles, preferably 1 to 30 moles, for 1 mole of the compound(V).

The reaction solvents include, for example, ethers (e.g., dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether), esters (e.g., ethyl formate, ethyl acetate, isopropyl acetate),halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbontetarachloride), hydrocarbons (e.g., n-hexane, benzene, toluene), amides(e.g., formamide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone), ketones (e.g., acetone, methyl ethyl ketone),nitriles (e.g., MeCN, propionitrile), acid (e.g., Hydrochloric acid,acetic acid, formic acid), dimethylsulfoxide, water, and a mixed solventthereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −80° C. to 80° C., more preferablyfrom about −20° C. to 60° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

Step 5

The compound (VI) is reacted with hydrohalic acid such as hydrochloricacid, etc. to give the compound (VII). Hydrohalic acid is generally usedin an amount of about 1 to 100 moles, preferably 1 to 30 moles, for 1mole of the compound (VI). The reaction solvents include, for example,ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methylether, diisopropyl ether), esters (e.g., ethyl formate, ethyl acetate,isopropyl acetate), halogenated hydrocarbons (e.g., dichloromethane,chloroform, carbon tetarachloride), hydrocarbons (e.g., n-hexane,benzene, toluene), amides (e.g., formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone), ketones (e.g., acetone,methyl ethyl ketone), nitriles (e.g., MeCN, propionitrile),dimethylsulfoxide, water, and a mixed solvent thereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −80° C. to 80° C., more preferablyfrom about −20° C. to 60° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

Step 6

The compound (VII) is reacted with a peroxyacid (e.g.,meta-Chloroperoxybenzoic acid, peroxyacetic acid), etc. to give thecrude sulfoxide compound. Furthermore, the crude sulfoxide compound isreacted with a base (e.g. triethylamine, sodium acetate, sodiumbicarbonate, sodium hydrogen carbonete) to give the single stereoisomersulfoxide compound (VIII).

Peroxyacid is generally used in an amount of about 1 to 100 moles,preferably 1 to 30 moles, for 1 mole of Compound (III). The reactionsolvents include, for example, alcohols (e.g., methanol, ethanol),halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbontetarachloride), hydrocarbons (e.g., n-hexane, benzene, toluene), amides(e.g., formamide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone). The reaction temperature is usually in the rangeof from about −100° C. to 100° C., preferably from about −80° C. to 50°C., more preferably from about −20° C. to 0° C. The reaction time mayvary according to the reagents, solvents or reaction temperature to beemployed, but usually is 0.5 to 24 hours.

Step 7

The compound (VIII) is reacted with a reductant (e.g., phosphorustrichloride, phosphorus tribromide) to give the compound (IX).

The reductant (e.g., phosphorus trichloride, phosphorus tribromide) isgenerally used in an amount of about 1 to 100 moles, preferably 1 to 30moles, for 1 mole of Compound (VIII).

The reaction solvents include, for example, halogenated hydrocarbons(e.g., dichloromethane, chloroform, carbon tetarachloride), hydrocarbons(e.g., n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone). Thereaction temperature is usually in the range of from about −100° C. to100° C., preferably from about −80° C. to 50° C., more preferably fromabout −60° C. to 0° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

Step 8

The compound (X) is obtained by subjecting Compound (IX) to a hydrolysisreaction to make amide on 7-side chain to an amino group, followed bytreating the compound with a hydrohalic acid such as hydrochloric acid.The reaction solvents include, for example, ethers (e.g., anisole,dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether,diisopropyl ether), esters (e.g., ethyl formate, ethyl acetate, n-butylacetate, isopropyl acetate), halogenated hydrocarbons (e.g.,dichloromethane, chloroform, carbon tetarachloride), hydrocarbons (e.g.,n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., MeCN,propionitrile), nitros (e.g., nitromethane, nitorethane, nitrobenzene),dimethylsulfoxide, water, and a mixed solvent selected from two or morethereof. The reaction temperature is usually in the range of from about−100° C. to 100° C., preferably from about −50° C. to 50° C., morepreferably from about −40° C. to 30° C. The reaction time may varyaccording to the reagents, solvents or reaction temperature to beemployed, but usually is 0.5 to 24 hours.

2) Formation of the 7-Saide Chain: Synthesis of the Compound (XII) Step9

The compound (X) is subjected to condensation reaction with the compound(XI) to give the compound (XII). The reaction solvents include, forexample, water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether,tert-butyl methyl ether, diisopropyl ether), esters (e.g., ethylformate, ethyl acetate, isopropyl acetate), halogenated hydrocarbons(e.g., dichloromethane, chloroform, carbon tetarachloride), hydrocarbons(e.g., n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., MeCN,propionitrile), dimethylsulfoxide, water, and a mixed solvent thereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −80° C. to 80° C., more preferablyfrom about −60° C. to 50° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

3) Formation of the 3-Side Chain: Synthesis of the Compound (I) Step 10

The compound (I′) is obtained by subjecting the compound (XII) to asubstitution reaction with the compound (XIII) and then subjecting it todeprotection reaction. The reaction solvents used in the reactionbetween the compound (XII) and the compound (XIII) include, for example,ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methylether, diisopropyl ether), esters (e.g., ethyl formate, ethyl acetate,isopropyl acetate), halogenated hydrocarbons (e.g., dichloromethane,chloroform, carbon tetarachloride), hydrocarbons (e.g., n-hexane,benzene, toluene), amides (e.g., formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone), ketones (e.g., acetone,methyl ethyl ketone), nitriles (e.g., MeCN, propionitrile),dimethylsulfoxide, water, and a mixed solvent thereof. The reactiontemperature is usually in the range of from about −100° C. to 100° C.,preferably from about −80° C. to 80° C., more preferably from about −20°C. to 30° C. The reaction time may vary according to the reagents,solvents or reaction temperature to be employed, but usually is 0.5 to24 hours.

The protecting group to be used in the above reaction such asamino-protecting groups, hydroxy-protecting groups, etc. includes, forexample, protecting groups described in Protective Groups in OrganicSynthesis, written by T. W. Greene, John Wiley & Sons Inc. (1991), etc.Methods for the introduction and removal of a protecting group aremethods commonly used in synthetic organic chemistry (see, for example,methods described in Protective Groups in Organic Synthesis, written byT. W. Greene, John Wiley & Sons Inc. (1991)), etc., or can be obtainedby a modified method thereof. Furthermore, a functional group includedin each substituent can be converted by a known method (e.g., thosedescribed in Comprehensive Organic Transformations, written by R. C.Larock (1989), etc.) in addition to the above production methods. Someof the compounds of the present invention can be used as a syntheticintermediate, leading to a new derivative. Intermediates and desiredcompounds produced in each of the above production methods can beisolated and purified by a purification method commonly used insynthetic organic chemistry, for example, neutralization, filtration,extraction, washing, drying, concentration, recrystallization, any kindof chromatography, etc. Furthermore, intermediates can be subjected to anext reaction without any purification.

Examples of an amino-protecting group include phthalimide, loweralkoxycarbonyl (butoxycarbonyl (Boc) etc.), lower alkenyloxycarbonyl(allyloxycarbonyl (Alloc), etc.), benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, optionally substituted aralkanoyl(p-nitrobenzoyl, etc.), acyl (formyl, chloroacetyl, etc.), optionallysubstituted aralkyl (trityl, etc.), benzhydryl (BH), and the like.

Examples of a hydroxy-protecting group include lower alkoxycarbonyl suchas a C1-C4 alkoxycarbonyl (e.g., t-butyloxycarbonyl), halogenated loweralkoxycarbonyl such as a halogenated (C1-C3) alkoxycarbonyl (e.g.,2-iodo ethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl), aryl-(lower)alkoxycarbonyl such as a phenyl-(C1-C4) alkoxycarbonyl having optionallya substituent (s) on the benzene ring (benzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl), p-methoxybenzyl (PMB), tri-lower alkylsilylsuch as tri-(C1-C4) alkylsilyl (e.g., trimethylsilyl,t-butyldimethylsilyl), a substituted methyl such as C1-C4 alkoxymethyl(e.g., methoxymethyl), C1-C4 alkoxy-(C1-C4) alkoxymethyl (e.g.,2-methoxyethoxymethyl), C1-C4 alkylthiomethyl (e.g., methylthiomethyl),tetrahydropyranyl, and the like.

The above-mentioned deprotecting reaction is carried out in a solventsuch as tetrahydrofuran, dimethylformamide, diethyl ether,dichloromethane, toluene, benzene, xylene, cyclohexane, hexane,chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane,acetone, acetonitrile, or a mixed solvent thereof, using a Lewis acid(e.g., AlCl3, SnCl4, TiCl4), a protonic acid (e.g., HCl, HBr, H2SO4,HCOOH), and the like.

The obtained compound is further chemically modified, and thereby anester, or a compound of which amino on the thiazole or thiadiazole ringat the 7-position thereof is protected, or a pharmaceutically acceptablesalt, or a solvate thereof can be synthesized.

wherein, P¹ and P² are protecting groups; Y is a leaving group (e.g., ahalogen (Cl, Br, I, F), methanesulfonyloxy, pe-toluenesulfoxy); R5 islower alkyl; other symbols are as defined above.

(1) Synthesis of the Compound (XV) Step 1

The compound (V) is reacted with a reductant (e.g., phosphorustrichloride, phosphorus tribromide), followed by treating the resultantwith a hydrohalic acid such as hydrochloric acid, etc. to give thecompound (IX)

The reaction solvents include, for example, ethers (e.g., dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether), esters (e.g., ethyl formate, ethyl acetate, isopropyl acetate),halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbontetarachloride), hydrocarbons (e.g., n-hexane, benzene, toluene), amides(e.g., formamide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone), ketones (e.g., acetone, methyl ethyl ketone),nitriles (e.g., MeCN, propionitrile), dimethylsulfoxide, water, and amixed solvent thereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −80° C. to 80° C., more preferablyfrom about −20° C. to 60° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

Step 2

The compound (XV) is obtained by subjecting Compound (XIV) to ahydrolysis reaction to make amide on 7-side chain to an amino group,followed by treating the compound with a hydrohalic acid such ashydrochloric acid. The reaction solvents include, for example, ethers(e.g., anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether), esters (e.g., ethyl formate, ethylacetate, n-butyl acetate, isopropyl acetate), halogenated hydrocarbons(e.g., dichloromethane, chloroform, carbon tetarachloride), hydrocarbons(e.g., n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., MeCN,propionitrile), nitros (e.g., nitromethane, nitorethane, nitrobenzene),dimethylsulfoxide, water, and a mixed solvent selected from two or morethereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −50° C. to 50° C., more preferablyfrom about −40° C. to 30° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

2) Formation of the 7-Saide Chain: Synthesis of the Compound (XVII) Step3

The compound (XV) is subjected to condensation reaction with thecompound (XI) to give the compound (XVI). The reaction solvents include,for example, water, ethers (e.g., dioxane, tetrahydrofuran, diethylether, tert-butyl methyl ether, diisopropyl ether), esters (e.g., ethylformate, ethyl acetate, isopropyl acetate), halogenated hydrocarbons(e.g., dichloromethane, chloroform, carbon tetarachloride), hydrocarbons(e.g., n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., MeCN,propionitrile), dimethylsulfoxide, water, and a mixed solvent thereof.

The reaction temperature is usually in the range of from about −100° C.to 100° C., preferably from about −80° C. to 80° C., more preferablyfrom about −60° C. to 50° C. The reaction time may vary according to thereagents, solvents or reaction temperature to be employed, but usuallyis 0.5 to 24 hours.

Step 4

The compound (XVII) is obtained by subjecting the compound (XVI) tooxidation reaction using an oxidation agent well-known to those skilledin the art (e.g., m-chloroperbenzoic acid, acetic peroxide).

The reaction solvents include, for example, ethers (e.g., anisole,dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether,diisopropyl ether), esters (e.g., ethyl formate, ethyl acetate, n-butylacetate, isopropyl acetate), halogenated hydrocarbons (e.g.,dichloromethane, chloroform, carbon tetarachloride), hydrocarbons (e.g.,n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., MeCN,propionitrile), nitros (e.g., nitromethane, nitorethane, nitrobenzene),dimethylsulfoxide, water, and a mixed solvent selected from two or morethereof. The reaction temperature is usually in the range of from about−100° C. to 100° C., preferably from about −80° C. to 50° C., morepreferably from about −60° C. to −30° C. The reaction time may varyaccording to the reagents, solvents or reaction temperature to beemployed, but usually is carried out for 0.5 to 24 hours.

The obtained compound (XVII) can be purified by column chromatography toobtain each 2-methyl stereoisomer.

3) Formation of the 3-Side Chain: Synthesis of the Compound (I) Step 5

Compound (I′) is obtained by subjecting Compound (XVII) to asubstitution reaction with Compound (XIII) by a method well-known tothose skilled in the art, followed by reducing it with a reduction agentwell-known to those skilled in the art (e.g., phosphorus chloride,phosphorus tribromide), and then subjecting it to a deprotectionreaction. The reaction solvents include, for example, ethers (e.g.,anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methylether, diisopropyl ether), esters (e.g., ethyl formate, ethyl acetate,n-butyl acetate, isopropyl acetate), halogenated hydrocarbons (e.g.,dichloromethane, chloroform, carbon tetarachloride), hydrocarbons (e.g.,n-hexane, benzene, toluene), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., MeCN,propionitrile), nitros (e.g., nitromethane, nitorethane, nitrobenzene),dimethylsulfoxide, water, and a mixed solvent selected from two or morethereof. The reaction temperature is usually in the range of from about−100° C. to 100° C., preferably from about −80° C. to 50° C., morepreferably from about −40° C. to 00° C. The reaction time may varyaccording to the reagents, solvents or reaction temperature to beemployed, but usually is 0.5 to 24 hours.

wherein, P2 is protecting groups; Y is a leaving group (e.g., a halogen(Cl, Br, I, F), methanesulfonyloxy, pe-toluenesulfoxy); other symbolsare as defined above.

(1) Synthesis of the Compound (I) Step 1

The compound (XVIII) is obtained by reaction of the compound (XI) andthe compound (I-H) as the similar procedure described in Step 9 ofScheme 1.

Step 2

The compound (I) is obtained by reaction of the compound (XVIII) and thecompound (XIII) as the similar procedure described in Step 10 of Scheme1.

The compounds of the present invention have a wide antimicrobialactivity spectrum, and may be used for prevention or therapy against avariety of diseases caused by causative bacteria in a variety of mammalsincluding humans, for example, airway infectious diseases, urinarysystem infectious diseases, respiratory system infectious diseases,sepsis, nephritis, cholecystitis, oral cavity infectious diseases,endocarditis, pneumonia, bone marrow membrane myelitis, otitis media,enteritis, empyema, wound infectious diseases, opportunistic infection,etc.

The compounds of the present invention exhibit high antimicrobialactivity in particular against Gram negative bacteria, preferably, Gramnegative bacteria of enterobacteria (E. coli, Klebsiella, Serratia,Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.), Gramnegative bacteria colonized in respiratory system (Haemophilus,Moraxella, etc.), and Gram negative bacteria of glucose non fermentation(Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa,Stenotrophomonas, Burkholderia, Acinetobacter, etc.). The compounds arestable against beta-lactamase belonging to Classes A, B, C and D whichis produced by these Gram negative bacteria, and have high antimicrobialactivity against a variety of beta-lactam drug resistant Gram negativebacteria, such as ESBL producing bacteria, etc. These are extremelystable against metallo-beta-lactamase belonging to Class B including inparticular IMP type, VIM type, L-1 type, etc. Thus, these are effectiveagainst a variety of beta-lactam drug resistant Gram negative bacteriaincluding Cephem and Carbapenem. Moreover, the compounds of the presentinvention have antimicrobial activity against Gram positive bacteriaincluding methicillin-resistant Staphylococcus aureus (MRSA),penicillin-resistant Streptococcus pneumoniae (PRSP), etc. Still morepreferable compounds have features regarding kinetics in the body, suchas high blood concentration, long duration of effects, and/orsignificant tissue migration. More preferable compounds are safe interms of side effects, such as fever and nephrotoxty. More preferablecompounds have high water solubility, and thus preferable as aninjecting drug, in particular.

The compounds of the present invention can be administered either orallyor parenterally. The compounds of the present invention, whenadministered orally, can be used in any dosage form of normalformulations, for example, solid drug such as tablet, powder, granule,capsule, etc.; solution drug; oleaginous suspension drug; or liquid drugsuch as syrup or elixir.

The compounds of the present invention, when administered parenterally,can be used as an aqueous or oleaginous suspended injecting agent, ornasal drops. In preparation thereof, a conventional excipient, binder,lubricant, aqueous solvent, oleaginous solvent, emulsifier, suspendingagent, preservative, stabilizer, etc. can be optionally used. Aformulation of the present invention is produced by combining (forexample, mixing) a therapeutically effective amount of a compound of thepresent invention with a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention may be administered eitherparenterally or orally as an injecting agent, capsules, tablets, andgranules, and preferably administered as an injecting agent. The dosageof the present compound may usually be, per 1 kg of body weight of apatient or animal, about 0.1 to 100 mg/day, preferably, about 0.5 to 50mg/day, if desired, divided into 2-4 times per day. Carriers when usedin an injecting agent are, for example, distilled water, brine, etc.,and a base and the like may be used for pH adjustment. When used ascapsules, granules, or tablets, carriers may be known excipients (e.g.,starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.),binders (e.g., starch, acacia gum, carboxymethyl cellulose,hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g.,magnesium stearate, talc, etc.), etc.

General Method

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification. Unlessotherwise indicated, all temparatures are expressed in ° C. (degreesCentigrade). Unless otherwise indicated, all reactions are conductedunder an inert atmosphere at ambient temperature.

All temperatures are given in degrees Celsius, all solvents are highestavailable purity and all reactions run under anhydrous conditions in anargon (Ar) or nitrogen (N2) atmosphere where necessary.

1H NMR (hereinafter also “NMR”) spectra were recorded on BruckerAVANCE-400 spectrometers. CDCI3 is deuteriochloroform, d6-DMSO ishexadeuteriodimethylsulfoxide, D20 is Deuterium oxide, and CD3OD istetradeuteriomethanol. Chemical shifts are expressed in parts permillion (ppm, 8 units). Coupling constants are in units of hertz (Hz).Splitting patterns describe apparent multiplicities and are designatedas s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet),m (muitiplet), br (broad).□

Mass spectra were run on Waters Open Architecture System, UPLC SQD MSanalytical system. The compound is analyzed using a reverse phasecolumn, e.g., Xbridge-C18, Sunfire-C18, Thermo Aquasil/Aquasil C18,Acquity HPLC C18, Acquity UPLC BEH C18, Shim-pack XR-ODS, ThermoHypersil Gold eluted using an acetonitrile and water gradient with a iowpercentage of an acid modifier such as 0.02% TFA or 0.1% formic acid.

Analytical HPLC was run using an Agilent system (1100 series) withvariable wavelength UV detection using Luna C18 column and eluting withan acetonitrile/water gradient containing a 0.05% or 0.1% TFA modifier(added to each solvent).

Unless otherwise indicated, flash chromatography was run on a TeledyneIsco Combiflash RF using disposable Redi-Sep flash columns (normal orreverse stationary phase as indicated), and a detector with UVwavelength at 254 nm. A styrenic adsorbent resin, DIAION™ HP20SS, wasused in the workup and purification of cephalosporin analogs, and isreferred to simply as HP20SS resin in the following examples.

EXAMPLES

Hereinafter, the present invention is described in more details withExamples, Reference Examples, Experiments and Formulation Examples.However, the present invention is not construed to be limited thereto.

The meaning of each abbreviation is as described below.

Ac: Acetyl Allooc: Allyloxycarbonyl BH or Bzh: Benzhydryl

Boc: tert-Butoxycarbonyl

Bn: Benzyl

Bt: benzotriazoleCbz: carbobenzoxy

DMF: N,N-dimethylformamide

EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et: Ethyl

HOBt: 1-hydroxybenzotriazolei-Pr: isopropylmCPBA: m-chloroperoxybenzoic acidMe: methyl

ODS: Octadecylsilyl

PMB: para-MethoxybenzylTBS: tert-butyldimethylsilylt-Bu: tert-butylTFA: trifluoroacetic acid

Tr: Trityl

WSCD: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimidert: room temperatureTFA: trifluoroacetic acidTHF: tetrahydrofuranDCM: dichloromethaneMeOH: methanolEA or EtOAc: ethyl acetatePd/C: palladium on carbonNaBH(OAc)₃: sodium triacetoxyborohydridePd₂(dba)₃: tris(dibenzylideneacetone)dipalladium (0)

XPhos:

dicyclohexyl[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphaneSEMCl: 2-(trimethylsilyl)ethoxymethyl chlorideCDI: 1,1′-carbonyldiimidazoleAlCl₃: aluminum chlorideLAH: lithium aluminium hydrideDIBAL-H: diisobutylaluminium hydridePyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphateHATU:2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (V)DIPEA or DIEA: diisopropylethylamineK₂CO₃: potassium carbonateTMS: tetramethylsilaneCDCl₃: deuteriochloroformCD₃OD: tetradeuteriomethanolDMSO-d₆: hexadeuteriodimethylsulfoxide

Reference Example 1 Synthesis of Compound X-1

Step (1): Compound X-1a→Compound X-1b

Compound X-1a (26.47 g, 51.2 mmol) which was synthesized according tothe synthesis in U.S. Pat. No. 4,463,172A1 was dissolved into dioxane(200 mL), and thereto was then added 4 mol/L hydrochloric acid solutionin dioxane (25.6 ml, 102 mmol) at rt. The mixture was stirred at rt for1 hour. The reaction mixture was concentrated under reduced pressure.The precipitated solid was then collected by filtration, and washed withdiisopropyl ether/dichloromethane to yield compound X-1b (21.1 g, 75%).

¹H-NMR (CDCl₃) δ: 7.37-7.26 (11H, m), 7.03-6.99 (2H, m), 6.87 (1H, s),6.36 (1H, d, J=8.7 Hz), 5.63-5.59 (1H, m), 5.23-5.20 (2H, m), 4.31 (1H,d, J=12.3 Hz), 4.09 (1H, d, J=12.3 Hz), 3.86 (2H, s), 1.99 (3H, s).

Step (2): Compound X-1b→Compound X-1c

Compound X-1b (5.53 g, 10 mmol) was dissolved into dichloromethane (60mL), and thereto was then added dropwise a solution ofm-chloroperoxybenzoic acid (3.45 g, 13 mmol) in dichloromethane (40 mL)at −40° C. The mixture was stirred at −40° C. for 1 hour. The reactionmixture was diluted with an aqueous sodium thiosulfate solution, thenseparated and washed with saturated sodium hydrogen carbonate solution,and dried over magnesium sulfate. Magnesium sulfate was filtrated off,and then the liquid was concentrated under reduced pressure. Theprecipitated solid was then collected by filtration, and washed withmethanol to yield compound X-1c (3.79 g, 67%).

MS (M+1)=569

Step (3): Compound X-1c→Compound X-1d

Compound X-1c (3.79 g, 6.6 mmol) was dissolved into dimethylformamide(35 mL), and thereto was then added phosphorus trichloride (1.7 mL, 20mmol) at −50° C. The mixture was stirred at −20° C. for 30 minutes. Thereaction mixture was diluted with water and ethyl acetate, thenseparated and washed with water and a saturated salt solution, and driedover magnesium sulfate. Magnesium sulfate was filtrated off, and thenthe liquid was concentrated under reduced pressure. Thecompound-containing liquid was subjected to silica gel columnchromatography to elute out the desired compound with hexane/ethylacetate. The desired-compound-containing fraction was concentrated underreduced pressure to yield compound X-1d (1.98 g, 54%).

MS (M+1)=553

Step (4): Compound X-1d→Compound X-1e

Phorphorus pentachloride (1.47 g, 7.1 mmol) was suspended intodichloromethane (20 mL), and thereto were then added pyridine (0.63 ml,7.8 mmol) and compound X-1d (1.95 g, 3.5 mmol) at 0° C. The mixture wasstirred at 0° C. for 1 hour. Thereto was then added methanol (10 mL) at−40° C. The mixture was stirred at 0° C. for 30 minutes. The mixture wasdiluted with a saturated sodium hydrogen carbonate solution anddichloromethane, then separated and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then ethyl acetate (20 ml) wasadded and concentrated under reduced pressure to yield the ethyl acetatesolution of compound X-1e. This solution was used as it was, withoutbeing purified, in the next reaction.

Step (5): Compound X-1e+Compound X-1f→Compound X-1g, Compound X-1h

Compound X-1f (1.82 g, 4.2 mmol) and triethylamine (0.68 mL, 4.9 mmol)were dissolved into dimethylacetoamide (20 mL), and thereto was thenadded methanesulfonyl chloride (0.36 mL, 4.6 mmol) at −20° C. Themixture was stirred at −10° C. for 20 minutes. Pyridine (0.57 mL, 7.1mmol) and the reaction mixture were added to the ethyl acetate solutionof compound X-1e (3.5 mmol) at 0° C. The mixture was stirred at 0° C.for 20 minutes. The reaction mixture was diluted with water and ethylacetate, then separated and washed with water and a saturated saltsolution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The compound-containing liquid was subjected to silica gelcolumn chromatography to elute out the desired compound withhexane/ethyl acetate. The desired-compound-containing fraction wasconcentrated under reduced pressure to yield Compound X-1g (0.13 g,4.4%), compound X-1h (1.17 g, 40%).

Compound X-1g

¹H-NMR (CDCl₃) δ: 8.18-8.16 (2H, m), 7.42-7.30 (11H, m), 6.93 (1H, s),6.03 (1H, dd, J=9.0, 5.0 Hz), 5.23 (1H, d, J=5.0 Hz), 4.83 (1H, d,J=12.3 Hz), 4.21 (1H, d, J=12.3 Hz), 4.01 (1H, q, J=7.2 Hz), 1.64 (3H,s), 1.61 (3H, s), 1.57 (3H, d, J=7.2 Hz), 1.53 (9H, s), 1.41 (9H, s).

Compound X-1h

¹H-NMR (CDCl₃) δ: 8.22-8.19 (2H, m), 7.46-7.30 (11H, m), 7.01 (1H, s),6.13 (1H, dd, J=9.0, 5.1 Hz), 5.19 (1H, d, J=5.1 Hz), 4.43 (1H, d,J=11.5 Hz), 4.18 (1H, d, J=11.5 Hz), 3.85 (1H, q, J=7.3 Hz), 1.63 (3H,s), 1.60 (3H, s), 1.58 (3H, d, J=7.3 Hz), 1.53 (9H, s), 1.39 (9H, s).

Step (6): Compound X-1g→Compound X-1 Compound X-1g (77.6 g, 92 mmol) wasdissolved into tetrahydrofuran (770 mL), and thereto was then addedsodium iodide (41.5 g, 277 mmol) at 15° C. The resultant solution wasstirred at 15° C. for 1 day. The reaction mixture was diluted with anaqueous sodium bisulfite solution and ethyl acetate, then separated andwashed with water and a saturated salt solution, and dried overmagnesium sulfate. Magnesium sulfate was filtrated off, and then theliquid was concentrated under reduced pressure to yield compound X-1(85.2 g, 99%). Compound X-1g yielded was used as it was, without beingpurified, in the next reaction.

¹H-NMR (CDCl₃) δ: 8.24 (1H, d, J=8.8 Hz), 7.42-7.29 (12H, m), 6.94 (1H,s), 5.94 (1H, dd, J=8.8, 4.9 Hz), 5.27 (1H, d, J=4.9 Hz), 4.97 (1H, d,J=9.8 Hz), 4.07-4.00 (2H, m), 1.64 (3H, s), 1.61 (3H, s), 1.55-1.53(12H, m), 1.41 (9H, s).

Reference Example 2 Synthesis of Compound X-2

Step (1): Compound X-1e+Compound X-2a→Compound X-2b

Compound X-1e (8.3 g, 15 mmol) and compound X-2a (10.4 g, 18 mmol) wereused to synthesize the target compound in the same way as in step 4 and5 of Reference Example 1.

Yielded amount: 10.4 g, (70%)

¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J=8.1 Hz), 8.09 (1H, s), 7.43-7.29 (11H,m), 7.23 (2H, d, J=8.5 Hz), 6.94 (1H, s), 6.82 (2H, d, J=8.5 Hz), 5.92(1H, dd, J=8.1, 4.9 Hz), 5.36 (1H, dd, J=8.4, 4.6 Hz), 5.23 (1H, d,J=4.9 Hz), 5.14 (1H, d, J=11.9 Hz), 5.05 (1H, d, J=11.9 Hz), 4.85 (1H,d, J=12.3 Hz), 4.23 (1H, d, J=12.3 Hz), 4.00 (1H, q, J=7.4 Hz), 3.76(3H, s), 2.92 (1H, dd, J=16.4, 8.4 Hz), 2.83 (1H, dd, J=16.4, 4.6 Hz),1.57 (3H, d, J=7.4 Hz), 1.54 (9H, s), 1.41 (9H, s).

Step (2): Compound X-2b→Compound X-2

Compound X-2b (10.4 g, 11 mmol) was used to synthesize the targetcompound in the same way as in step 6 of Reference Example 1.

Yielded amount: 10.7 g, (95%) ¹H-NMR (CDCl₃) δ: 8.30 (1H, d, J=7.9 Hz),8.11 (1H, s), 7.44-7.29 (11H, m), 7.23 (2H, d, J=8.7 Hz), 6.95 (1H, s),6.82 (2H, d, J=8.7 Hz), 5.84 (1H, dd, J=7.9, 4.8 Hz), 5.37 (1H, dd,J=8.3, 4.8 Hz), 5.27 (1H, d, J=4.8 Hz), 5.14 (1H, d, J=11.8 Hz), 5.05(1H, d, J=11.8 Hz), 4.99 (1H, d, J=9.8 Hz), 4.06-4.01 (2H, m), 3.76 (3H,s), 2.92 (1H, dd, J=16.4, 8.3 Hz), 2.84 (1H, dd, J=16.4, 4.8 Hz),1.54-1.52 (12H, m), 1.41 (9H, s).

Reference Example 3 Synthesis of Compound X-3 and X-24

Step (1): Compound X-3a→Compound X-3b→Compound X-3c

To a pre-cooled solution of compound X-3a (50 g, 97 mmol), which wassynthesized according to the synthesis in Tetrahedron Letter, 37,1971-1974 (1996), in dichloromethane (450 mL) at −10° C. was addedperacetic acid (19.82 g, 102 mmol, 37% Wt). The mixture was stirred at−10 to −5° C. To the resulting mixture was added a solution of sodiumbisulfite (12.1 g, 116 mmol) in water (200 mL). Water (150 mL) was addedto the mixture, and then an organic layer was separated. The organiclayer was washed with water (250 mL), 10% aqueous solution of sodiumchloride (250 mL). The aqueous layers were successively extracted withdichloromethane (150 mL). The combined organic layers were dried overmagnesium sulfate and filtered. To the filtrated was addeddimethylformamide (200 mL) and then the solution was concentrated. Theresidue was placed in a reaction bottle with dimethylformamide (30 mL)and then to the solution was added formaldehyde (15.7 g, 194 mmol, 37%Wt) and dimethylamine hydrochloride (7.89 g, 97 mmol). The mixture wasstirred at 60° C. for 3 hours and then cooled in ice bath. To themixture was added water (250 mL) dropwise over 8 minutes. The resultingmixture was stirred for 3.5 hr. The precipitated material was collectedby filtration and washed with water (250 mL) and ethanol (250 mL). Thesolid was dried under air for 3 days to afford compound X-3c (48.5 g,92%).

¹H-NMR (DMSO-D₆) δ: 8.61 (1H, d, J=8.3 Hz), 7.39-7.35 (3H, m), 6.98-6.93(4H, m), 6.40 (1H, s), 6.21 (1H, s), 5.95 (1H, dd, J=8.3, 5.1 Hz),5.31-5.26 (2H, m), 5.21 (1H, d, J=11.9 Hz), 5.07 (1H, d, J=5.1 Hz), 4.74(1H, d, J=12.5 Hz), 3.91 (1H, d, J=15.4 Hz), 3.83 (1H, d, J=15.4 Hz),3.75 (3H, s), 1.96 (3H, s).

Step (2): Compound X-3c→Compound X-3d→Compound X-3e

To a pre-cooled suspension of compound X-3c (25.0 g, 45.9 mmol) in1,4-dioxane (175 mL) and dichloromethane (50 mL) in ice bath was addedzinc (15.01 g, 230 mmol) with dichloromethane (15 mL). To the mixture inice bath was added concentrated hydrochloric acid (19.1 mL, 230 mmol, 12M) dropwise over 45 minutes and then washed with dichloromethane (10mL). The mixture was stirred in ice bath for 1 hour, and then filteredthrough Celite and it washed with dichloromethane (300 mL). The filtratewas washed with water (500 mL) and water (125 mL) successively. Theaqueous layers were successively extracted with dichloromethane (75 mL).The combined organic layers were dried over magnesium sulfate, filteredand concentrated. The residue was dissolved with 1,4-dioxane (75 mL) toremove dichloromethane and then cooled in ice bath. To the mixture wasadded hydrochloric acid in 1,4-dioxane (23.0 mL, 4M) and then stirred inice bath for 2 hr. To the resulting mixture was added isopropyl ether(122 mL) and stirred in ice bath for 1.5 hr. The precipitated materialwas collected by filtration and washed with isopropyl ether. The solidwas dried under air over night to afford compound X-3e (15.3g, 58%).

¹H-NMR (DMSO-D₆) δ: 9.27 (1H, d, J=7.8 Hz), 7.38-7.34 (3H, m), 6.97-6.92(4H, m), 5.48 (1H, dd, J=7.8, 3.8 Hz), 5.19 (1H, d, J=3.8 Hz), 5.15-5.08(3H, m), 4.64 (1H, d, J=12.2 Hz), 4.31 (1H, d, J=12.2 Hz), 3.77-3.74(5H, m), 2.04 (3H, s).

Step (3): Compound X-3e→Compound X-3f

To a pre-cooled suspension of compound X-3e (50.0 g, 94 mmol) indichloromethane (500 mL) in ice bath was added peracetic acid (18.4 g,94 mmol, 39% Wt) dropwise over 10 minutes. The mixture was stirred inice bath for 3 hours. An aqueous solution of sodium bisulfite (11.8 g,113 mmol) in water (250 mL) was added. Water (250 mL) was further added.The organic layer was washed with water (500 mL) and 10% aqueoussolution of sodium chloride (500 mL). The aqueous layers weresuccessively extracted with dichloromethane (50 mL). The combinedorganic layers were concentrated while replaced a solvent toacetonitrile by adding twice (250 mL, 100 mL). To the residualsuspension (approx. 250 mL) was added acetonitrile (612 mL) and water(150 mL). To the mixture was added 10% aqueous solution of sodiumacetate (100 mL) and then pH showed 6.29. The mixture was stirred atroom temperature with monitoring pH for 1.5 hours. 2 mol/L hydrochloricacid (24.5 mL) was added to quench. The insoluble material was collectedby filtration and washed with water (200 mL) and acetonitrile (150 mL).The solid was dried under air over 3 days to afford compound X-3f (32.6g, 66%).

¹H-NMR (DMSO-D₆) δ: 8.53 (1H, d, J=8.3 Hz), 7.38-7.36 (3H, m), 6.97-6.93(4H, m), 5.88 (1H, dd, J=8.3, 4.9 Hz), 5.30 (1H, d, J=12.0 Hz), 5.21(1H, d, J=12.0 Hz), 5.10 (1H, d, J=4.9 Hz), 4.81 (1H, d, J=12.3 Hz),4.42 (1H, d, J=12.3 Hz), 3.90-3.79 (3H, m), 3.76 (3H, s), 1.61 (3H, d,J=7.5 Hz).

Step (4): Compound X-3f→Compound X-3g

To a pre-cooled suspension of compound X-3f (30.0 g, 57.4 mmol) indimethylformamide (240 mL) with stirring at −40° C. was added phosphorustrichloride (23.6 g, 172 mmol) over 10 minutes. The mixture was stirredat −35° C. for 1 hour. To the resulting mixture was addeddichloromethane (300 mL) and water (300 mL). The organic layer wasseparated, and then washed with water (300 mL) and 10% aqueous solutionof sodium chloride (300 mL). The aqueous layers were successivelyextracted with dichloromethane (90 mL). The combined organic layers weredried over magnesium sulfate, filtered and concentrated to approx. 150mL. To the residual suspension was added 2-propanol (180 mL) and thenthe suspension was concentrated to approx. 150 mL again. To the residuewas added 2-propanol (14 mL) and diisopropyl ether (120 mL). The mixturewas stirred for 3 hours. The insoluble material was collected byfiltration and dried under air for 3 days to afford compound X-3g(20.8g, 71%).

¹H-NMR (DMSO-D₆) δ: 9.21 (1H, d, J=8.4 Hz), 7.38-7.34 (3H, m), 6.96-6.91(4H, m), 5.73 (1H, dd, J=8.4, 5.0 Hz), 5.33 (1H, d, J=5.0 Hz), 5.27 (1H,d, J=11.9 Hz), 5.17 (1H, d, J=11.9 Hz), 4.66 (1H, d, J=12.0 Hz), 4.49(1H, d, J=12.0 Hz), 4.08 (1H, q, J=7.2 Hz), 3.75 (5H, s), 1.53 (3H, d,J=7.2 Hz).

Step (5): Compound X-3g→Compound X-3h

To a pre-cooled suspension of phosphorus pentachloride (8.21 g, 39.4mmol) in dichloromethane (90 mL) with stirring at −5° C. was addedpyridine (3.43 g, 43.4 mmol) and compound X-3g (10.0 g, 19.7 mmol). Themixture was stirred at 10 to 15° C. for 1 hour. The resulting mixturewas poured into pre-cooled methanol (25 mL) in ice bath, and then water(50 mL) was added. The organic layer was separated and washed with water(100 mL). The aqueous layers were successively extracted withdichloromethane (40 mL). The combined organic layers were dried overmagnesium sulfate, filtered. To the filtrate was added p-toluenesulfonicacid mono-hydrate (3.75 g, 19.7 mmol) and ethyl acetate (60 mL). Themixture was concentrated to remove dichloromethane. To the residualsuspension was added ethyl acetate (50 mL). The mixture was stirred at35° C., and then stirred in ice bath for 2.5 hours. The insolublematerial was collected by filtration and washed with ethyl acetate. Thesolid was dried through air circulation to afford compound X-3h (7.30 g,63%).

¹H-NMR (DMSO-D₆) δ: 9.02 (3H, br s), 7.48 (2H, d, J=7.7 Hz), 7.36 (2H,d, J=8.3 Hz), 7.12 (2H, d, J=7.7 Hz), 6.94 (2H, d, J=8.3 Hz), 5.45 (1H,d, J=5.0 Hz), 5.29-5.17 (3H, m), 4.68 (1H, d, J=12.0 Hz), 4.51 (1H, d,J=12.0 Hz), 4.21 (1H, q, J=7.2 Hz), 3.75 (3H, s), 2.29 (3H, s), 1.57(3H, d, J=7.2 Hz).

Step (6): Compound X-3h+Compound X-1f→Compound X-3

To a pre-cooled suspension of compound X-1f (9.29 g, 21.6 mmol) andcompound X-3h (12.0 g, 21.6 mmol) in ethyl acetate (120 mL) at −40° C.was added phenyl dichlorophosphate (6.84 g, 4.82 mmol) and N-methylmorpholine (7.65 g, 76 mmol). The mixture was stirred at −40° C. for 1.5hours. 0.5 mol/L hydrochloric acid (130 mL) was added to quench. Theorganic layer was separated and washed with water (120 mL), 5% aqueoussolution of sodium bicarbonate (120 mL), and 10% aqueous solution ofsodium chloride (120 mL). The aqueous layers were successively extractedwith ethyl acetate (60 mL). The combine organic layers were dried overmagnesium sulfate, filtered and concentrated to give a crude material(19.7g) 6.58 g of the crude residue was purified by silica gel columnchromatography eluted with n-hexane and ethyl acetate to afford compoundX-3 (5.77 g).

¹H-NMR (DMSO-D₆) δ: 11.84 (1H, s), 9.58 (1H, d, J=8.3 Hz), 7.36 (2H, d,J=8.2 Hz), 7.26 (1H, s), 6.94 (2H, d, J=8.2 Hz), 5.87 (1H, dd, J=8.1,5.0 Hz), 5.40 (1H, d, J=4.9 Hz), 5.26 (1H, d, J=11.8 Hz), 5.18 (1H, d,J=11.8 Hz), 4.67 (1H, d, J=12.2 Hz), 4.48 (1H, d, J=12.0 Hz), 4.06 (1H,q, J=7.2 Hz), 3.76 (3H, s), 1.52 (3H, d, J=7.2 Hz), 1.46-1.44 (15H, m),1.39 (9H, s).

Step (7): Compound X-3→Compound X-24

Compound X-3 (25.6 g, 30.0 mmol) was used to synthesize Compound X-24 inthe same way as in step (6) of Reference Example 1.

Yielded amount: 28.08 g, (106%)

¹H-NMR (CDCl₃) δ: 8.14 (1H, d, J=8.9 Hz), 7.35-7.33 (3H, m), 6.91 (2H,d, J=8.4 Hz), 5.91 (1H, dd, J=8.9, 4.9 Hz), 5.27 (1H, d, J=11.9 Hz),5.21-5.18 (2H, m), 5.05 (1H, d, J=10.4 Hz), 4.09-4.07 (2H, m), 3.82 (3H,s), 1.62 (3H, s), 1.60 (3H, s), 1.55 (3H, d, J=7.3 Hz), 1.53 (9H, s),1.41 (9H, s).

Reference Example 4 Synthesis of Compound X-4

Step (1): Compound X-3h+Compound X-2a→Compound X-4a

Compound X-3h (6.3 g, 11 mmol) and compound X-2a (6.0 g, 11 mmol) wereused to synthesize the target compound in the same way as in step 6 ofReference example 3.

Yielded amount: 6.7 g, (65%)

¹H-NMR (DMSO-DE) δ: 11.87 (1H, s), 9.68 (1H, d, J=8.2 Hz), 7.36 (2H, d,J=8.0 Hz), 7.31-7.29 (3H, m), 6.94 (2H, d, J=8.0 Hz), 6.87 (2H, d, J=8.0Hz), 5.84 (1H, dd, J=8.2, 4.8 Hz), 5.39 (1H, d, J=4.8 Hz), 5.26 (1H, d,J=12.0 Hz), 5.18 (1H, d, J=12.0 Hz), 5.10 (2H, s), 4.96 (1H, t, J=6.4Hz), 4.68 (1H, d, J=12.0 Hz), 4.49 (1H, d, J=12.0 Hz), 4.07 (1H, q,J=7.2 Hz), 3.75 (3H, s), 3.73 (3H, s), 2.92-2.80 (2H, m), 1.51 (3H, d,J=7.2 Hz), 1.47 (9H, s), 1.35 (9H, s).

Step (2): Compound X-4a→Compound X-4

Compound X-4a (28.3 g, 30 mmol) was used to synthesize the targetcompound X-4 in the same way as in step 6 of Reference Example 1.

Yielded amount: 32 g, (103%)

¹H-NMR (CDCl₃) δ: 8.21 (1H, d, J=8.0 Hz), 8.11 (1H, s), 7.37-7.35 (3H,m), 7.23 (2H, d, J=8.7 Hz), 6.92 (2H, d, J=8.7 Hz), 6.83 (2H, d, J=8.7Hz), 5.81 (1H, dd, J=8.0, 4.8 Hz), 5.36 (1H, dd, J=8.2, 5.0 Hz),5.30-5.04 (7H, m), 4.09-4.03 (1H, m), 3.82 (3H, s), 3.79 (3H, s), 2.89(1H, dd, J=16.4, 8.2 Hz), 2.82 (1H, dd, J=16.4, 5.0 Hz), 1.55-1.54 (12H,m), 1.40 (9H, s).

Reference Example 5 Synthesis of Compound X-5

Step (1): Compound X-5a→Compound X-5

Compound X-5a (2.1 g, 5 mmol) was suspended into toluene (20 mL), andthereto was then added quinuclidin-4-ylmethanamine (0.74 g, 5.3 mmol) at0° C. The mixture was stirred at 50° C. for 1 hour. Thereto was addedacetic acid (0.57 mL, 10 mmol). The resultant was stirred at reflux for3 days. The reaction mixture was diluted with ethyl acetate and aqueoussodium hydroxide solution, then separated and washed with water and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The precipitated solid was then collected byfiltration, and washed with diisopropyl ether to yield compound X-5 (2.6g, 95%).

¹H-NMR (CDCl3) δ: 7.35 (4H, d, J=8.7 Hz), 7.33 (2H, s), 6.90 (4H, d,J=8.7 Hz), 5.18 (4H, s), 3.82 (6H, s), 3.38 (2H, br s), 2.85-2.81 (6H,m), 1.42-1.38 (6H, m).

Reference Example 6 Synthesis of Compound X-6

Step (1): Compound X-5a→Compound X-6

Compound X-5a (2.1 g, 5 mmol) was used to synthesize Compound X-6 in thesame way as Reference Example 5.

Yielded amount: 2.18 g (80%)

¹H-NMR (CDCl₃) δ: 7.36-7.32 (4H, m), 7.27 (2H, s), 6.91-6.87 (4H, m),5.16 (4H, s), 4.59-4.49 (1H, m), 3.81 (6H, s), 3.24-3.20 (2H, m),2.32-2.24 (2H, m), 2.20 (3H, s), 2.15-2.11 (2H, m), 1.88-1.82 (2H, m),1.72-1.67 (2H, m).

Reference Example 7 Synthesis of Compound X-7

Step (1): Compound X-7a→Compound X-7

Compound X-7a (0.48 mg, 4.2 mmol) and triethylamine (0.58 ml, 4.2 mmol)were dissolved into dimethylacetamide (12 mL), and thereto was thenadded Methanesulfonyl chloride (0.3 ml, 3.9 mmol) at −20° C. The mixturewas stirred at −20° C. for 30 minutes. Thereto was then addedaminoethylpyrrolidine (0.48 g, 4.2 mmol) at 0° C. The mixture wasstirred at 0° C. for 1 hours. The reaction mixture was diluted withethyl acetate, washed with an aqueous sodium hydroxide solution, waterand a saturated salt solution, and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The compound-containing liquid wassubjected to silica gel column chromatography to elute out the desiredcompound with hexane/ethyl acetate (containing 3% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound X-7 (0.75 g, 45%).

¹H-NMR (CDCl₃) δ: 7.62 (1H, d, J=8.7 Hz), 7.47-7.42 (1H, m), 7.34 (4H,dd, J=8.7, 2.3 Hz), 6.95-6.90 (3H, m), 6.85-6.81 (2H, m), 5.11 (2H, s),4.96 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.49 (2H, q, J=5.9 Hz),2.72-2.65 (2H, m), 2.58-2.50 (4H, m), 1.83-1.74 (4H, m).

Reference Example 8 Synthesis of Compound X-8

Step (1): Compound X-7a→Compound X-8

Compound X-7a (0.5 g, 3.9 mmol) was used to synthesize Compound X-7 inthe same way as Reference Example 7.

Yielded amount: 0.62 g (39%)

¹H-NMR (DMSO-D₆) δ: 7.69-7.65 (1H, m), 7.47-7.45 (2H, m), 7.39 (1H, d,J=8.8 Hz), 7.31-7.26 (2H, m), 7.01-6.97 (2H, m), 6.87-6.83 (2H, m), 5.25(2H, s), 4.91 (2H, s), 3.78 (3H, s), 3.74 (3H, s), 3.08-2.89 (7H, m),1.97-1.69 (6H, m).

Reference Example 9 Synthesis of Compound X-9

Step (1): Compound X-7a→Compound X-9

Compound X-7a (0.5 g, 3.9 mmol) was used to synthesize Compound X-9 inthe same way as Reference Example 7.

Yielded amount: 0.64 g (43%)

¹H-NMR (CDCl₃) δ: 7.69 (1H, d, J=8.9 Hz), 7.34 (4H, t, J=8.2 Hz), 6.99(1H, d, J=8.9 Hz), 6.93 (2H, d, J=8.7 Hz), 6.83 (2H, d, J=8.7 Hz), 5.13(2H, s), 4.95 (2H, s), 4.72-4.55 (1H, m), 3.84 (3H, s), 3.80 (3H, s),3.77-3.61 (1H, m), 3.14-2.94 (3H, m), 2.32-2.03 (3H, m), 1.92-1.76 (3H,m), 1.50-1.34 (1H, m).

Reference Example 10 Synthesis of Compound X-10

Step (1): Compound X-21→Compound X-10

Compound X-21 (1.9 g, 5.0 mmol) and diisopropylethylamine (1.3 ml, 7.5mmol) were dissolved into dichloromethane (25 mL), and thereto was thenadded diphenyl chlorophosphate (1.2 ml, 6.5 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 hour. Thereto was then addedaminoethylpyrrolidine (0.68 g, 6 mmol) at 0° C. The mixture was stirredat rt for 2 hours. The reaction mixture was diluted with ethyl acetate,washed with an aqueous sodium hydroxide solution, water and a saturatedsalt solution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The compound-containing liquid was subjected to silica gelcolumn chromatography to elute out the desired compound withhexane/ethyl acetate (containing 3% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound X-10 (0.56 g, 19%).

¹H-NMR (DMSO-D₆) δ: 8.85 (1H, t, J=5.8 Hz), 7.58-7.32 (12H, m), 5.25(2H, s), 5.22 (2H, s), 3.37-3.35 (2H, m), 2.56-2.54 (2H, m), 1.72-1.65(3H, m).

The compounds shown below were used to synthesize the each targetcompound in the same way as Reference Example 10.

Reference Example 11 Synthesis of Compound X-11

Yielded amount: 0.37 g (15%)

¹H-NMR (DMSO-D₆) δ: 7.49-7.21 (15H, m), 5.28 (2H, s), 5.23 (2H, s),2.99-2.72 (7H, m), 2.02-1.55 (6H, m).

Reference Example 12 Synthesis of Compound X-12

Yielded amount: 0.52 g (20%)

¹H-NMR (DMSO-D₆) δ: 8.82 (1H, t, J=6.3 Hz), 7.57-7.20 (10H, m), 5.24(2H, s), 5.23 (2H, s), 3.02 (2H, d, J=6.4 Hz), 2.74-2.70 (6H, br m),1.33-1.29 (6H, br m).

Reference Example 13 Synthesis of Compound X-13

Yielded amount: 0.88 g (36%)

¹H-NMR (DMSO-D₆) δ: 7.49-7.32 (12H, m), 5.28 (2H, s), 5.24 (2H, s),3.41-2.82 (8H, m), 2.14-1.63 (5H, m).

Reference Example 14 Synthesis of Compound X-14

Yielded amount: 1.0 g (39%)

¹H-NMR (CDCl₃) δ: 7.97 (1H, br s), 7.93-7.90 (1H, m), 7.56-7.30 (10H,m), 5.25 (2H, s), 5.16 (2H, s), 4.16-4.11 (1H, m), 3.24 (1H, br s),2.34-2.18 (6H, m), 1.84-1.71 (5H, m).

Reference Example 15 Synthesis of Compound X-15

Yielded amount: 0.85 g (50%)

[M+H]=537.25

Reference Example 16 Synthesis of Compound X-16

Yielded amount: 2.0 g (71%)

¹H-NMR (CDCl₃) δ: 7.41 (1H, s), 7.36-7.27 (5H, m), 6.91 (2H, d, J=8.4Hz), 6.81 (2H, d, J=8.4 Hz), 6.28 (1H, br s), 5.06 (2H, s), 5.02 (2H,s), 3.82 (3H, s), 3.78 (3H, s), 3.19 (2H, d, J=6.3 Hz), 2.90-2.86 (6H,m), 1.41-1.38 (6H, m).

Reference Example 17 Synthesis of Compound X-17

Yielded amount: 1.3 g (49%)

¹H-NMR (CDCl₃) δ: 7.34 (4H, dd, J=8.8, 2.6 Hz), 7.11 (1H, d, J=1.9 Hz),7.02 (1H, d, J=1.9 Hz), 6.91 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz),5.06 (2H, br s), 5.00 (2H, br s), 3.98 (1H, s), 3.83 (3H, d, J=10.2 Hz),3.80 (3H, s), 3.54 (2H, s), 3.25 (1H, s), 2.82 (2H, s), 2.42 (6H, dd,J=53.5, 20.3 Hz).

Reference Example 18 Synthesis of Compound X-18

Yielded amount: 0.39 g (32%)

[M+H]=521.35

Reference Example 19 Synthesis of Compound X-19

Yielded amount: 1.3 g (50%)

¹H-NMR (CDCl₃) δ: 7.34 (2H, dd, J=11.5, 2.8 Hz), 7.31-7.27 (2H, m), 7.24(1H, d, J=1.6 Hz), 7.01 (1H, dd, J=10.4, 1.9 Hz), 6.92 (2H, dt, J=9.3,2.4 Hz), 6.82 (2H, dt, J=9.2, 2.4 Hz), 5.95 (1H, t, J=6.1 Hz), 5.08 (4H,s), 3.82 (3H, s), 3.79 (3H, s), 3.20 (2H, d, J=6.4 Hz), 2.91-2.87 (6H,m), 1.42-1.38 (6H, m).

Reference Example 20 Synthesis of Compound X-20

Yielded amount: 1.1 g (42%)

¹H-NMR (CDCl₃) δ: 7.33 (4H, dd, J=13.7, 8.6 Hz), 6.91-6.79 (6H, m), 5.05(4H, s), 4.00-3.89 (1H, m), 3.82 (3H, s), 3.77 (3H, dd, J=18.3, 6.6 Hz),3.59 (1H, t, J=20.3 Hz), 3.21 (1H, d, J=28.7 Hz), 2.85 (1H, s), 2.57(1H, d, J=39.9 Hz), 2.35 (3H, s), 1.81 (5H, s).

Reference Example 21 Synthesis of Compound X-21

Step (1): Compound X-21a→Compound X-21b

Compound X-21a (13.5 g, 38 mmol) was suspended into dichloromethane (100mL), and thereto were then added N,O-Dimethylhydroxylamine hydrochloride(5.6 g, 57 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (11 g, 57 mmol) and triethylamine (7.94 ml, 57 mmol) inturn. The mixture was stirred at rt for 1 hours. The reaction mixturewas diluted with dichloromethane and water. The resultant solution wasthen separated and washed with water and a saturated salt solution, anddried over magnesium sulfate. Magnesium sulfate was filtrated off, andthen the liquid was concentrated under reduced pressure. Theprecipitated solid was then collected by filtration, and washed withdiisopropyl ether to yield compound X-21b (15.1 g, 100%).

¹H-NMR (CDCl₃) δ: 7.42-7.26 (12H, m), 7.16 (2H, d, J=10.4 Hz), 5.17 (2H,s), 5.13 (2H, s), 3.48 (3H, s), 3.32 (3H, s).

Step (2): Compound X-21b→Compound X-21c

Compound X-21b (15.1 g, 38 mmol) was suspended into tetrahydrofurane(320 mL), and thereto was then added methyl magnesium bromide (0.99mol/L in tetrahydrofurane, 77 ml 76 mmol) at 0° C. The mixture wasstirred at rt for 1 hours. The reaction mixture was diluted withsaturated ammonium chloride solution, then extracted ethyl acetate andwashed with water and a saturated salt solution, and dried overmagnesium sulfate. Magnesium sulfate was filtrated off, and then theliquid was concentrated under reduced pressure. The precipitated solidwas then collected by filtration, and washed with diisopropyl ether toyield compound X-21c (13 g, 97%).

¹H-NMR (CDCl₃) δ: 7.44-7.26 (12H, m), 5.21 (2H, s), 5.16 (2H, s), 2.52(3H, s).

Step (2): Compound X-21c→Compound X-21

Compound X-21c (13 g, 37 mmol) was dissolved into pyridine (200 mL), andthereto was then added selenium dioxide (10.3 g, 93 mmol).

The mixture was stirred at 80° C. for 1 day. The reaction mixture wasfiltered and evaporated. The residue was diluted with aqueoushydrochloric acid solution and ethyl acetate, then separated and washedwith water and a saturated salt solution, and dried over magnesiumsulfate. Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The precipitated solid was thencollected by filtration, and washed with diisopropyl ether to yieldcompound X-21 (11.5 g, 82%).

¹H-NMR (DMSO-D₆) δ: 7.52-7.48 (3H, m), 7.44-7.32 (9H, m), 5.27 (2H, s),5.23 (2H, s).

Reference Example 22 Synthesis of Compound X-22

Step (1): Compound X-1g→Compound X-22

A solution of the Compound X-1g (4.20 g, 5.0 mmol) in dichloromethane(20 ml) was cooled to −40° C. A solution of m-chloroperbenzoic acid(1.46 g, 5.5 mmol) in dichloromethane (20 ml) was added drop-wise. Afterstirring at −40° C. for 30 minutes, aqueous 15% sodium thiosulfatesolution was added thereto, dichloromethane was evaporated under reducedpressure, followed by extraction with ethyl acetate. The organic layerwas washed with aqueous 5% sodium hydrogen carbonate, then saturatedbrine, and then dried with anhydrous magnesium sulfate. The inorganicsubstance was removed by filtration, followed by concentration in vacuo.The resulting crude product was purified by silica gel columnchromatography to yield Compound X-22 as a yellow form.

Yield: 2.59 g, (60%)

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.59 (3H, s), 1.60 (3H, s), 1.61 (9H,s), 1.78 (3H, d, J=7.53 Hz), 3.48 (1H, q, J=7.53 Hz), 4.05 (1H, d,J=12.67 Hz), 4.74 (1H, dd, J=4.96, 1.38 Hz), 5.17 (1H, d, J=12.67 Hz),6.25 (1H, dd, J=9.98, 4.96 Hz), 6.95 (1H, s), 7.28-7.44 (11H, m), 8.09(1H, d, J=9.98 Hz), 8.30 (1H, s).

Reference Example 23 Synthesis of Compound X-23

Step (1): Compound X-1h→Compound X-23

From Compound X-1h (4.20 g, 5.0 mmol), Compound X-23 was obtained as awhite solid using the same method as Reference Example 22.

Yield: 2.26 g, (53%)

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=7.47 Hz), 1.42 (9H, s), 1.53 (9H, s),1.59 (3H, s), 1.60 (3H, s), 3.88 (1H, q, J=7.47 Hz), 4.34 (1H, d,J=12.05 Hz), 4.59 (1H, d, J=5.03 Hz), 4.63 (1H, d, J=12.05 Hz), 6.31(1H, dd, J=9.76, 5.03 Hz), 7.00 (1H, s), 7.25-7.48 (11H, m), 7.95 (1H,d, J=9.76 Hz), 8.19 (1H, s).

Reference Example 25 Synthesis of Compound X-25 [Chemical Formula 142]

compoundX-25:5-chloro-1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

To a solution of5-chloro-1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (WO2013052568A1, 8 g, 14.93 mmol) and(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine, 2 Hydrochloride (3.34g, 15.7 mmol) in DCM (700 mL) were added DIPEA (9.12 mL, 52.2 mmol) andPyBOP (9.32 g, 17.9 mmol) at room temperature. The reaction mixture wasstirred overnight and then concentrated, and the resulting residue waspurified via automated silica gel chromatography (120 g column, 0-10%MeOH in DCM). The isolated product was purified again via automatedsilica gel chromatography (24 g column, 0-10% MeOH in DCM) to affordcompound X-25 (4.64 g, 47% yield) as a white solid. LCMS: (M+H)⁺: 658.2.¹H NMR (DMSO-d₆): 10.46 (d, J=7.3 Hz, 1H), 8.57 (s, 1H), 7.67 (s, 1H),7.50 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H),6.87 (d, J=8.6 Hz, 2H), 5.35 (s, 2H), 4.91 (s, 2H), 4.04 (q, J=6.8 Hz,1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.62-3.69 (m, 1H), 3.02-3.16 (m, 2H),2.21 (s, 3H), 1.90-2.15 (m, 6H), 1.60 (d, J=13.9 Hz, 2H), 1.25-1.35 (m,2H), 0.99-1.07 (m, 2H).

Reference Example 26 Synthesis of Compound X-26 [Chemical Formula 144]

Compound X-26:5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-N-((R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

To a solution of5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (WO2013052568A1, 10.0 g, 19.1 mmol) and(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine, 2 Hydrochloride (4.07g, 19.1 mmol) in DCM (800 mL) were added DIPEA (11.7 mL, 66.8 mmol) andPyBOP (11.92 g, 22.90 mmol) at room temperature, and the reactionmixture was stirred for 0.5 h. The mixture was concentrated and theobtained residue was purified via automated silica gel chromatography(120 g column, 0-10% MeOH in DCM). The fractions containing product werecombined and washed with saturated NaHCO₃ aq, brine, and watersuccessively. The product was repurified via automated silica gelchromatography (24 g column, 0-10% MeOH in DCM) to afford compound X-26(5.95 g, 48% yield) as a white solid. LCMS: (M+H)⁺: 646.2. ¹H NMR(CDCl₃) δ: 10.71 (d, J=6.6 Hz, 1H), 8.64 (s, 1H), 7.41 (d, J=8.6 Hz,2H), 7.37 (d, J=8.6 Hz, 2H), 6.96 (d, J=9.1 Hz, 2H), 6.87 (d, J=8.6 Hz,1H), 6.81 (s, 1H), 5.22 (s, 2H), 5.01 (s, 2H), 4.31 (q, J=6.4 Hz, 1H),4.17 (q, J=7.3 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.40-3.55 (m, 2H),2.58-2.73 (m, 2H), 2.55 (s, 3H), 2.31-2.41 (m, 2H), 2.20-2.30 (m, 2H),2.01 (d, J=14.9 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

Example 1 Synthesis of Compound I-1

Step (1): Compound 1a→Compound 1b

Compound 1a (14.53 g, 74.8 mmol) was dissolved into dichloromethane (150m), and thereto was then added dropwise boron tribromide (50g, 200 mmol)at 0° C. The mixture was stirred at rt for 1 if mixture was diluted withice water and evaporated. The precipitated solid was then collected byfiltration, and washed with water. In this way, compound 1b was yielded(11.2 g, 90%).

¹H-NMR (DMSO-D) δ: 10.18 (1H, s), 9.66 (1H, s), 7.06 (1H, s), 6.92 (1H,s), 5.16 (2H, s).

Step (2): Compound 1a→Compound 1b

Compound 1a (14.53 g, 74.8 mmol) was dissolved into dichloromethane (150mL), and thereto was then added dropwise boron tribromide (50g, 200mmol) at 0° C. The mixture was stirred at rt for 1 hour. The reactionmixture was diluted with ice water, and evaporated. The precipitatedsolid was then collected by filtration, and washed with water. In thisway, compound 1b was yielded (11.2g, 90%).

¹H-NMR (DMSO-D₆) δ: 10.18 (1H, s), 9.66 (1H, s), 7.06 (1H, s), 6.92 (1H,s), 5.16 (2H, s).

Step (2): Compound 1b→Compound 1c

Compound 1b (13.20 g, 79 mmol) was dissolved into dimethylacetoamide(130 mL), and thereto were then added potassium carbonate (32.9 g, 238mmol), p-methoxybenzyl chloride (26.0 ml, 191 mmol) and sodium iodide(11.91 g, 79 mmol) in turn. The mixture was stirred at 50° C. for 1hour. The reaction mixture was poured into water. The precipitated solidwas then collected by filtration, and washed with water and diisopropylether. In this way, compound 1c was yielded (37.32 g 116%).

¹H-NMR (CDCl₃) δ: 7.37-7.33 (5H, m), 6.92-6.88 (5H, m), 5.16 (2H, s),5.16 (2H, s), 5.12 (2H, s), 3.82 (3H, s), 3.81 (3H, s).

Step (3): Compound 1c→Compound 1d

A 2 mol/L aqueous sodium hydroxide solution (119 ml, 237 mmol) was addedto a solution of the total amount of compound 1c yielded (37.32g, 79mmol) in tetrahydrofuran (30 mL) and methanol (30 mL). The resultantsolution was stirred at 70° C. for 1 hour. To the reaction mixture wasadded water and 2 mol/L aqueous hydrochloric acid solutions (120 mL).The precipitated solid was then collected by filtration, and washed withwater to yield compound 1d (42.71 g, 127%).

¹H-NMR (CDCl₃) δ: 7.69 (1H, s), 7.36-7.34 (4H, m), 7.02 (1H, s),6.91-6.87 (4H, m), 5.15 (2H, s), 5.09 (2H, s), 4.73 (2H, s), 4.69 (1H,br s), 3.81 (3H, s), 3.80 (3H, s).

Step (4): Compound 1d→Compound 1e

The total amount of compound 1d yielded (42.71 g, 79 mmol) was suspendedinto acetone (350 mL), and thereto was then added Jone's reagent (2.67mol/L, 71.0 mL, 190 mmol) at 0° C. The mixture was stirred at 0° C. for1 hour. The reaction mixture was diluted with dichloromethane and water,then added sodium bisulfite at 0° C. The resultant solution was thenseparated and washed with water and a saturated salt solution, and driedover magnesium sulfate. Magnesium sulfate was filtrated off, and thenthe liquid was concentrated under reduced pressure. The precipitatedsolid was then collected by filtration, and washed with diisopropylether to yield compound 1e (26.94 g, 81%).

¹H-NMR (CDCl₃) δ: 7.38 (2H, s), 7.35 (4H, d, J=8.1 Hz), 6.92 (4H, d,J=8.1 Hz), 5.21 (4H, s), 3.82 (6H, s).

Step (5): Compound 1e→Compound 1f

Compound 1e (1.88 g, 4.5 mmol) was suspended into toluene (20 mL), andthereto was then added aminoethylpyrrolidine (0.60 mL, 4.7 mmol) at 0°C. The mixture was stirred at rt for 30 minutes. Thereto was addedacetic acid (0.28 mL, 4.9 mmol). The resultant mixture was stirred atreflux for 30 minutes. The reaction mixture was diluted with ethylacetate and aqueous sodium hydroxide solution, then separated and washedwith water and a saturated salt solution, and dried over magnesiumsulfate. Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The precipitated solid was thencollected by filtration, and washed with diisopropyl ether to yieldcompound if (2.10 g, 91%).

¹H-NMR (CDCl3) δ: 7.36-7.32 (6H, m), 6.92-6.89 (4H, m), 5.17 (4H, s),3.81 (6H, s), 3.78-3.73 (2H, m), 2.72-2.68 (2H, m), 2.56 (4H, br s),1.74 (4H, br s).

Step (6): Compound X-1+Compound 1f→Compound 1g→Compound I-1

Compound if (517 mg, 1.0 mmol) was added to a solution of compound X-1(932 mg, 1.00 mmol) in dimethylformamide (2 mL) at 0° C., and theresultant solution was stirred at 0° C. for 1 day. The reaction mixturewas slowly added to a 5% salt solution (30 ml) (containing 1.5 g ofsodium bisulfite) at 0° C. The precipitated solid was collected byfiltration, washed with water, and then suspended into water. Thesuspension was freeze-dried to yield compound 1g as an orange solid.Compound 1g yielded was used as it was, without being purified, in thenext reaction.

The total amount of compound 1g yielded was dissolved in dichloromethane(10 mL), and the solution was cooled to −40° C. Thereto were then addedanisole (1.3 mL, 12 mmol) and a 2 mol/L aluminum chloride solution (6.00mL, 12 mmol) in nitromethane in turn. The resultant was stirred at 0° C.for 30 minutes. The reaction mixture was dissolved in water, a 2 mol/Laqueous hydrochloric acid solution, and acetonitrile. The resultantsolution was then washed with diisopropyl ether. To the water phase wasadded HP20-SS resin, and then acetonitrile was distilled off underreduced pressure. The resultant mixed liquid was purified by ODS columnchromatography. To the resultant target-compound solution was addedHP20-SS resin, and then acetonitrile was distilled off under reducedpressure. The resultant mixed liquid was purified by HP20-SS columnchromatography. To the resultant target-compound solution was added a0.2 N aqueous sodium hydroxide solution until the whole gave a pH of6.0. Thereafter, a piece of dry ice was added thereto. The resultantsolution was concentrated under reduced pressure, and then freeze-driedto yield compound I-1 as an orange powder.

Yielded amount: 163.5 mg, (18%).

¹H-NMR (D₂O) δ: 6.99 (3H, s), 5.80 (1H, d, J=4.6 Hz), 5.47 (1H, d, J=4.6Hz), 5.07 (1H, d, J=14.1 Hz), 4.30 (1H, d, J=14.1 Hz), 4.11 (1H, d,J=6.3 Hz), 4.00 (2H, br s), 3.69-3.52 (6H, m), 2.23 (4H, br s), 1.59(3H, d, J=5.8 Hz), 1.53 (3H, s), 1.51 (3H, s).

Elem. Anal.: C32H34N7O11S2Na(H2O) 4.8

Calcd.: C, 44.37; H, 5.07; N, 11.32; S, 7.40; Na, 2.65(%).

Found: C, 44.29; H, 4.98; N, 11.52; S, 7.27; Na, 2.76(%).

Example 2 Synthesis of Compound I-2

Step (1): Compound 2a→Compound 2b

Compound 2a (2.33 g, 10.2 mmol) was used to synthesize the targetcompound in the same way as step 1 of Example 1.

Yielded amount: 2.00 g, (98%)

¹H-NMR (DMSO-D₆) δ: 10.55 (2H, br s), 7.09 (1H, s), 5.22 (2H, s).

Step (2): Compound 2b→Compound 2c

Compound 2b (2.00 g, 9.97 mmol) was used to synthesize the targetcompound in the same way as step 2 of Example 1.

Yielded amount: 4.85 g (110%)

¹H-NMR (CDCl₃) δ: 7.39-7.37 (3H, m), 7.31 (2H, d, J=8.7 Hz), 6.94 (2H,d, J=8.7 Hz), 6.83 (2H, d, J=8.7 Hz), 5.18 (2H, s), 5.11 (2H, s), 5.09(2H, s), 3.84 (3H, s), 3.80 (3H, s).

Step (3): Compound 2c→Compound 2d

The total amount of compound 2c yielded (4.85 g, 9.97 mmol) was used tosynthesize the target compound in the same way as step 3 of Example 1.

Yielded amount: 4.46 g, (98%)

¹H-NMR (CDCl₃) δ: 7.62 (1H, s), 7.36 (2H, d, J=8.5 Hz), 7.33 (2H, d,J=8.5 Hz), 6.92 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 5.09 (2H, s),5.04 (2H, s), 4.99 (2H, s), 3.83 (3H, s), 3.80 (3H, s).

Step (4): Compound 2d→Compound 2e

Compound 2d (4.46 g, 9.72 mmol) was used to synthesize the targetcompound in the same way as step 4 of Example 1.

Yielded amount: 3.32 g, (75%, containing compound 2c)

Compound 2e yielded was used as it was, without being purified, in thenext reaction.

Step (5): Compound 2e→Compound 2f

Compound 2e (2.36 g, 5.19 mmol) was used to synthesize the targetcompound in the same way as in step 5 of Example 1.

Yielded amount: 0.98 g, (34%)

¹H-NMR (CDCl₃) δ: 7.39-7.36 (3H, m), 7.30 (2H, d, J=8.7 Hz), 6.94 (2H,d, J=8.7 Hz), 6.82 (2H, d, J=8.7 Hz), 5.16 (2H, s), 5.03 (2H, s), 3.84(3H, s), 3.80-3.77 (5H, m), 2.73 (2H, t, J=6.8 Hz), 2.61-2.56 (4H, m),1.77-1.74 (4H, m).

Step (6): Compound X-1+Compound 2f→Compound 2g

Compound X-1 (932 mg, 1.00 mmol) and compound 2f (551 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 124.3 mg (13%)

¹H-NMR (D₂O) δ: 7.31 (1H, dd, J=7.78, 1.53 Hz), 7.07 (1H, dd, J=7.78,1.53 Hz), 6.98 (1H, s), 6.83 (1H, t, J=7.78 Hz), 5.89 (1H, d, J=4.96Hz), 5.38 (1H, d, J=4.96 Hz), 4.31 (1H, t, J=7.32 Hz), 4.11-3.94 (4H,m), 3.51 (1H, d, J=17.23 Hz), 3.11 (3H, br s), 2.83-2.72 (2H, m),2.61-2.41 (5H, m), 2.19 (1H, br s), 2.13 (1H, br s), 1.52 (3H, s), 1.50(3H, s).

Elem. Anal.: C32H32.8ClN7O11S2Na1.2(H2O) 6.7

Calcd.: C, 40.92; H, 4.96; Cl, 3.77; N, 10.44; S, 6.83; Na, 2.94(%).

Found: C, 40.77; H, 4.91; Cl, 3.53; N, 10.72; S, 6.99; Na, 2.94(%).

Example 3 Synthesis of Compound I-3

Step (1): Compound 3a→Compound 3b

Compound 3a (60 g, 140 mmol) was suspended into dichloromethane (300mL), and thereto were then added N,O-Dimethylhydroxylamine hydrochloride(16.5 g, 169 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (32.2 g, 168 mmol) in turn. The mixture was stirred at rtfor 1 day. Thereto were then added N,O-Dimethylhydroxylaminehydrochloride (4.10 g, 42 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.05 g, 42mmol) in turn. The mixture was stirred at rt for 3 hours. Thereto werethen added N,O-Dimethylhydroxylamine hydrochloride (4.10 g, 42 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.05 g, 42mmol) in turn. The mixture was stirred at rt for 2 hours. The reactionmixture was diluted with dichloromethane and water. The resultantsolution was then separated and washed with water and a saturated saltsolution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The precipitated solid was then collected by filtration, andwashed with diisopropyl ether to yield compound 3b (62.07 g, 94%).

¹H-NMR (CDCl₃) δ: 7.36-7.32 (4H, m), 7.02 (1H, d, J=8.4 Hz), 6.93-6.89(3H, m), 6.81 (2H, d, J=8.5 Hz), 5.06 (2H, s), 4.98 (2H, s), 3.83 (3H,s), 3.79 (3H, s), 3.45-3.31 (6H, br m).

Step (2): Compound 3b→Compound 3c

Compound 3b (18.88 g, 40 mmol) was suspended into tetrahydrofurane (380mL), and thereto was then added methyl magnesium bromide (0.99 mol/L intetrahydrofurane, 81 ml 80 mmol) at 0° C. The mixture was stirred at rtfor 3 hours. The reaction mixture was diluted with a saturated ammoniumchloride solution, then extracted ethyl acetate and washed with waterand a saturated salt solution, and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The precipitated solid was thencollected by filtration, and washed with diisopropyl ether to yieldcompound 3c (13.19 g, 77%).

¹H-NMR (CDCl₃) δ: 7.39-7.33 (5H, m), 6.93-6.91 (3H, m), 6.83 (2H, d,J=8.5 Hz), 5.09 (2H, s), 4.96 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 2.62(3H, s).

Step (3): Compound 3c→Compound 3d

Compound 3c (13.19 g, 31 mmol) was dissolved into pyridine (130 mL), andthereto was then added selenium dioxide (8.57 g, 77 mmol). The mixturewas stirred at 80° C. for 1 day. The reaction mixture was filtered andevaporated. The residue was diluted with an aqueous hydrochloric acidsolution and ethyl acetate, then separated and washed with water and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The precipitated solid was then collected byfiltration, and washed with diisopropyl ether to yield compound 3d(12.41 g, 88%).

¹H-NMR (DMSO-D) δ: 7.60 (1H, d, J=8.8 Hz), 7.46 (2H, d, J=8.5 Hz), 7.37(1H, d, J=8.8 Hz), 7.28 (2H, d, J=8.5 Hz), 6.99 (2H, d, J=8.5 Hz), 6.85(2H, d, J=8.5 Hz), 5.24 (2H, s), 4.92 (2H, s), 3.78 (3H, s), 3.74 (3H,s).

Step (4): Compound 3d→Compound 3e

Compound 3d (2.28 g, 5.0 mmol) was dissolved into dimethylacetoamide (20mL), and thereto were then added 4-aminomethylquinuclidine (2.10 g, 15.0mmol), hydroxybenzotriazole (0.74 g, 5.50 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g,5.50 mmol) in turn. The mixture was stirred at rt for 1 day and 40° C.for 1 day. The reaction mixture was diluted with an aqueous hydrochloricacid solution and stirred at rt for 30 minutes. The reaction mixture wasdiluted with ethyl acetate and aqueous sodium hydroxide solution, thenseparated and washed with water and a saturated salt solution, and driedover magnesium sulfate. Magnesium sulfate was filtrated off, and thenthe liquid was concentrated under reduced pressure. The precipitatedsolid was then collected by filtration, and washed with ethyl acetate toyield compound 3e (0.50 g, 17%).

¹H-NMR (DMSO-D₆) δ: 8.80 (1H, t, J=6.4 Hz), 7.50 (1H, d, J=8.8 Hz), 7.46(2H, d, J=8.7 Hz), 7.33 (1H, d, J=8.8 Hz), 7.28 (2H, d, J=8.7 Hz), 6.99(2H, d, J=8.7 Hz), 6.85 (2H, d, J=8.7 Hz), 5.22 (2H, s), 4.90 (2H, s),3.78 (3H, s), 3.74 (3H, s), 3.01 (2H, d, J=6.4 Hz), 2.81 (6H, t, J=7.6Hz), 1.37 (6H, t, J=7.6 Hz).

Step (2): Compound X-1+Compound 3e→Compound 3f

Compound X-1 (745 mg, 0.80 mmol) and compound 3e (463 mg, 0.80 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 284.2 mg (35%)

¹H-NMR (D₂O) δ: 7.31 (1H, d, J=8.7 Hz), 7.01 (1H, s), 6.88 (1H, d, J=8.7Hz), 5.84 (1H, d, J=4.8 Hz), 5.45 (1H, d, J=4.8 Hz), 4.65 (1H, d, J=14.4Hz), 4.11-4.05 (2H, m), 3.60-3.42 (6H, m), 3.36 (2H, s), 1.95 (6H, t,J=7.8 Hz), 1.57 (3H, d, J=6.9 Hz), 1.52 (3H, s), 1.51 (3H, s).

Elem. Anal.: C34H37ClN7O11S2Na(H2O) 6.4

Calcd.: C, 42.65; H, 5.24; Cl, 3.70; N, 10.24; S, 6.70; Na, 2.40(%).

Found: C, 42.61; H, 5.26; Cl, 3.83; N, 10.32; S, 6.71; Na, 2.43(%).

Example 4 Synthesis of Compound I-4

Step (1): Compound 1e+Compound 4a→Compound 4b

Compound 1e (1.88 g, 4.5 mmol) was dissolved into ethanol (10 mL), andthereto was then added Compound 4a (0.58 g, 4.5 mmol). The mixture wasstirred at rt for 1 day. The precipitated solid was then collected byfiltration, and washed with ethanol and diisopropyl ether to yieldcompound 4b (2.00 g, 84%).

¹H-NMR (CDCl₃) δ: 7.80 (1H, s), 7.32 (2H, d, J=8.5 Hz), 7.08 (2H, d,J=8.5 Hz), 6.73 (2H, d, J=8.5 Hz), 6.69 (2H, d, J=8.5 Hz), 6.49 (1H, brs), 5.01 (2H, s), 4.65 (2H, s), 4.35 (2H, br s), 3.78 (3H, s), 3.76 (3H,s), 3.27-3.01 (6H, br m), 1.90 (4H, br s).

Step (2): Compound X-1+Compound 4b→Compound 4c

Compound X-1 (932 mg, 1.00 mmol) and compound 4b (532 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 64.5 mg (6%)

¹H-NMR (D₂O) δ: 7.31 (1H, s), 7.15 (1H, s), 6.98 (1H, s), 5.79 (1H, d,J=4.8 Hz), 5.45 (1H, d, J=4.8 Hz), 5.03 (1H, d, J=14.2 Hz), 4.45 (2H, d,J=4.6 Hz), 4.25 (1H, d, J=14.2 Hz), 4.01 (1H, q, J=7.0 Hz), 3.81-3.43(6H, m), 2.24-2.06 (4H, m), 1.51-1.49 (9H, m).

Elem. Anal.: C32H34.5N8011S2Na1.5(H2O) 10.3

Calcd.: C, 38.77; H, 5.60; N, 11.30; S, 6.47; Na, 3.48(%).

Found: C, 38.76; H, 5.45; N, 11.42; S, 6.34; Na, 3.49(%).

Example 5 Synthesis of Compound I-5

Step (1): Compound 5a→Compound 5b

Compound 5a (8.50 g, 50 mmol) and hydroxylamine hydrochloride (5.21 g,75 mmol) were dissolved into ethanol (50 mL) and water (25 ml), andthereto was then added sodium carbonate (10.6 g, 100 mmol) at 0° C. Themixture was stirred at reflux for 1 hour. The reaction mixture wasdiluted with ethyl ether and aqueous sodium hydroxide solution, thenseparated and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The residue was distilled by vacuum distillation (4 mmHg, 116°C.) to yield compound 5b (1.88 g, 29%).

¹H-NMR (CDCl₃) δ: 3.09 (2H, br s), 2.75 (2H, br s), 2.57 (4H, br s),1.78 (4H, br s).

Step (2): Compound 5b+Compound 1e→Compound 5c

Compound 1e (2.10 g, 5.0 mmol) was dissolved into ethanol (10 mL), andthereto was then added Compound 5b (0.65 g, 5.0 mmol). The mixture wasstirred at rt for 1 day, 50° C. for 2 hours and 80° C. for 4 hours. Theprecipitated solid was then collected by filtration, and washed withethanol and diisopropyl ether to yield compound 5c (1.81 g, 68%).

¹H-NMR (CDCl₃) δ: 7.69 (1H, s), 7.61 (1H, s), 7.39-7.36 (4H, m),6.92-6.89 (4H, m), 5.23 (2H, s), 5.19 (2H, s), 4.19 (2H, t, J=6.7 Hz),3.81 (6H, s), 2.90 (2H, br s), 2.60 (4H, br s), 1.77 (4H, br s).

Step (3): Compound X-1+Compound 5c→Compound 5d

Compound X-1 (932 mg, 1.00 mmol) and compound 5c (533 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 158.9 mg, (14%)

¹H-NMR (D₂O) δ: 7.47 (1H, s), 7.40 (1H, s), 7.02 (1H, s), 5.81 (1H, d,J=4.8 Hz), 5.48 (1H, d, J=4.8 Hz), 5.04 (1H, d, J=14.3 Hz), 4.63-4.58(1H, m), 4.32 (1H, d, J=14.2 Hz), 4.08 (1H, q, J=7.0 Hz), 3.89-3.49 (6H,m), 2.22 (4H, br s), 1.58 (3H, d, J=7.2 Hz), 1.52 (3H, s), 1.50 (3H, s).

Elem. Anal.: C32H33.8N7O12S2Na1.2(H2O) 8.3

Calcd.: C, 40.47; H, 5.35; N, 10.32; S, 6.75; Na, 2.90(%).

Found: C, 40.39; H, 5.30; N, 10.59; S, 6.64; Na, 3.02(%).

Example 6 Synthesis of Compound I-6

Step (1): Compound 6a→Compound 6b

Compound 6a (2.81 g, 9.11 mmol) was dissolved into dichloromethane (30mL), and thereto was then added dropwise boron tribromide (2.5 ml, 26.4mmol) at 0° C. The mixture was stirred at rt for 1 hour. Thereto wasthen added dropwise methanol (10 ml, 247 mmol) at 0° C. The mixture wasstirred at 0° C. for 10 minutes. The reaction mixture was evaporated. Inthis way, compound 6b was yielded (5.53g, 168%). Compound 6b yielded wasused as it was, without being purified, in the next reaction.

Step (2): Compound 6b→Compound 6c

The total amount of compound 6b yielded (5.53g, 9.11 mmol) andtriethylamine (5.68 mL, 41.0 mmol) were dissolved into dichloromethane(30 mL), and thereto were then added di-t-butyl dicarbonate (6.35 ml,27.3 mmol) and N,N-dimethyl-4-aminopyridine (0.06 g, 0.5 mmol) in turnat 0° C. The mixture was stirred at rt for 1 day. The reaction mixturewas diluted with dichloromethane, washed with an aqueous sodiumhydroxide solution, water and a saturated salt solution, and dried overmagnesium sulfate. Magnesium sulfate was filtrated off, and then theliquid was concentrated under reduced pressure. The compound-containingliquid was subjected to silica gel column chromatography to elute outthe desired compound with hexane/ethyl acetate (containing 3% triethylamine). The desired-compound-containing fraction was concentrated underreduced pressure to yield compound 6c (1.27 g, 29%).

¹H-NMR (CDCl₃) δ: 7.89 (1H, s), 7.47 (1H, s), 4.00 (2H, t, J=6.0 Hz),2.82 (2H, t, J=6.0 Hz), 2.62 (4H, br s), 1.82 (4H, br s), 1.56 (18H, s).

Step (3): Compound X-1+Compound 5c→Compound 5d

Compound X-1 (932 mg, 1.00 mmol) and compound 5c (481 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 175.2 mg (18%)

¹H-NMR (D₂O) δ: 7.33 (1H, s), 7.15 (1H, s), 7.02 (1H, s), 5.80 (1H, d,J=4.8 Hz), 5.46 (1H, d, J=4.8 Hz), 4.47-4.25 (3H, m), 4.04 (1H, br s),3.72-3.47 (6H, m), 2.22 (4H, br s), 1.56-1.50 (9H, m).

Elem. Anal.: C31H34N7O10S3Na(H2O) 7.4

Calcd.: C, 40.60; H, 5.36; N, 10.69; S, 10.49; Na, 2.51(%).

Found: C, 40.65; H, 5.22; N, 10.88; S, 10.20; Na, 2.51(%).

Example 7 Synthesis of Compound I-7

Step (1): Compound 7a+Compound 7b→Compound 7c

Compound 7a (10.0 g, 41.6 mmol) was suspended into dichloromethane (100mL), and thereto was then added 1-chloro-N,N,2-trimethyl-1-propenylamine (6.1 mL, 45.8 mmol) at 0° C. The mixture wasstirred at rt for 1 hour. The reaction mixture was added to the mixtureof Compound 7b (23.90 g, 125 mmol) and sodium bicarbonate (17.65 g, 167mmol) in tetrahydrofurane (100 ml) and water (100 ml) at 0° C. Themixture was stirred at rt for 1 hour. The reaction mixture was dilutedwith an aqueous hydrochloric acid solution (adjusted pH=5) and ethylacetate, then separated and washed with water and a saturated saltsolution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure.

The compound-containing liquid was subjected to silica gel columnchromatography to elute out the desired compound with hexane/ethylacetate. The desired-compound-containing fraction was concentrated underreduced pressure to yield compound 7c (15.5 g, 101%).

¹H-NMR (CDCl₃) δ: 7.39 (1H, s), 6.51 (1H, s), 4.02-3.98 (4H, m), 3.89(3H, s), 3.82 (3H, s), 0.89 (9H, s), 0.09 (6H, s).

Step (2): Compound 7c→Compound 7d

Compound 7c (14.5 g, 39.0 mmol) and triphenylphosphine (12.28 g, 46.8mmol) were dissolved into tetrahydrofurane (150 mL), and thereto wasthen added dropwise dimethyl azodicarboxylate (2.7 mol/L in toluene,17.35 ml, 46.8 mmol) at 0° C. The mixture was stirred at rt for 2 hour.Thereto was then added dropwise a mixture of acetic acid and methanol(1:1) at 0° C. The mixture was stirred at 0° C. for 10 minutes. Thereaction mixture was diluted with a saturated sodium hydrogen carbonatesolution and toluene, then separated and washed with a saturated saltsolution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The residue was dissolved into toluene (150 mL) and hexane(100 ml) and stored at −20° C. for over night. The reaction mixture wasfiltered and washed with toluene/hexane (1/1).

The compound-containing liquid was subjected to silica gel columnchromatography to elute out the desired compound with hexane/ethylacetate. The desired-compound-containing fraction was concentrated underreduced pressure to yield compound 7d (6.37 g, 46%)

¹H-NMR (CDCl₃) δ: 7.17 (1H, s), 6.67 (1H, s), 4.11 (2H, t, J=5.8 Hz),3.95 (3H, s), 3.93-3.90 (5H, m), 0.83 (9H, s), −0.01 (6H, s).

Step (3): Compound 7d→Compound 7e

Triphenylphosphine (7.09 g, 27.0 mmol) was dissolved intodichloromethane (60 ml), and thereto was then added dropwise bromine(1.30 ml, 25.3 mmol) at 0° C. The mixture was stirred at rt for 20 min.Thereto was then added a solution of Compound 7d (6.37 g, 18.0 mmol) indichloromethane (20 ml) at 0° C. The resulting mixture was stirred atrt. for 2 hr. The reaction mixture was diluted with water anddichloromethane, then separated and washed with a saturated sodiumhydrogen carbonate solution and a saturated salt solution, and driedover magnesium sulfate.

Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The compound-containing liquid wassubjected to silica gel column chromatography to elute out the desiredcompound with hexane/ethyl acetate. The desired-compound-containingfraction was concentrated under reduced pressure to yield compound 7e(4.41 g, 81%).

¹H-NMR (CDCl₃) δ: 7.17 (1H, s), 6.69 (1H, s), 4.37 (2H, t, J=6.8 Hz),3.96 (3H, s), 3.91 (3H, s), 3.64 (2H, t, J=6.8 Hz).

Step (4): Compound 7e→Compound 7f

Compound 7e (4.41 g, 14.6 mmol) was used to synthesize the targetcompound in the same way as step 1 of Example 1.

Yielded amount: 3.80 g, (95%)

¹H-NMR (DMSO-D₆) δ: 9.91 (2H, br s), 6.94 (1H, s), 6.73 (1H, s), 4.24(2H, br s), 3.76 (2H, br s).

Step (5): Compound 7f→Compound 7g

Compound 7f (3.80 g, 13.87 mmol) was used to synthesize the targetcompound in the same way as step 2 of Example 1.

Yielded amount: 7.25 g, (102%)

¹H-NMR (CDCl₃) δ: 7.36-7.33 (4H, m), 7.23 (1H, s), 6.93-6.87 (4H, m),6.71 (1H, s), 5.13 (2H, s), 5.06 (2H, s), 4.33 (2H, t, J=6.8 Hz), 3.82(3H, s), 3.81 (3H, s), 3.60 (2H, t, J=6.8 Hz).

Step (6): Compound 7g→Compound 7h

Compound 7g (3.50 g, 6.80 mmol) was dissolved into dimethylacetoamide(35 ml), and thereto were then added pyrrolidine (1.13 ml, 13.61 mmol)and sodium iodide (1.02 g, 6.80 mmol) at 0° C. The mixture was stirredat rt for 1 day. The reaction mixture was diluted with ethyl acetate andan aqueous sodium hydroxide solution, then separated and washed withwater and a saturated salt solution, and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The compound-containing liquid wassubjected to amino silica gel column chromatography to elute out thedesired compound with hexane/ethyl acetate. Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 7h (0.62 g, 18%).

¹H-NMR (CDCl₃) δ: 7.36-7.33 (4H, m), 7.22 (1H, s), 6.92-6.86 (4H, m),6.70 (1H, s), 5.12 (2H, s), 5.06 (2H, s), 4.08 (2H, t, J=6.7 Hz), 3.82(3H, s), 3.81 (3H, s), 2.84 (2H, t, J=6.7 Hz), 2.57 (4H, br s), 1.76(4H, br s).

Step (7): Compound X-1+Compound 7h→Compound 7i

Compound X-1 (932 mg, 1.00 mmol) and compound 7h (505 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 292.8 mg, (33%)

¹H-NMR (D₂O) δ: 7.13 (1H, s), 7.01 (1H, s), 6.83 (1H, s), 5.81 (1H, d,J=4.8 Hz), 5.46 (1H, d, J=4.8 Hz), 5.05 (1H, d, J=14.3 Hz), 4.62-4.45(2H, m), 4.29 (1H, d, J=14.3 Hz), 4.06 (1H, q, J=7.0 Hz), 3.91-3.71 (3H,m), 3.58 (2H, br s), 3.51-3.44 (1H, m), 2.22 (4H, br s), 1.56 (3H, d,J=7.0 Hz), 1.52 (3H, s), 1.50 (3H, s).

Elem. Anal.: C31H34N7O11S2Na(H2O) 5.7

Calcd.: C, 42.77; H, 5.26; N, 11.26; S, 7.37; Na, 2.64(%).

Found: C, 42.50; H, 5.22; N, 11.55; S, 7.40; Na, 2.70(%).

Example 8 Synthesis of Compound I-8

Step (1): Compound 8a→Compound 8b

Compound 8a (21.4 g, 50 mmol) was used to synthesize the target compoundin the same way as step 1 of Example 3.

Yielded amount: 21.27 g, (90%)

¹H-NMR (CDCl₃) δ: 7.40 (1H, d, J=1.9 Hz), 7.37-7.33 (4H, m), 7.29 (1H,d, J=1.9 Hz), 6.92 (2H, d, J=8.7 Hz), 6.83 (2H, d, J=8.5 Hz), 5.07 (2H,s), 5.03 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.52 (3H, s), 3.34 (3H,s).

Step (2): Compound 8b→Compound 8c

Compound 8b (21.27 g, 45 mmol) was used to synthesize the targetcompound in the same way as step 2 of Example 3.

Yielded amount: 17.17 g, (89%)

¹H-NMR (CDCl₃) δ: 7.58 (1H, d, J=2.0 Hz), 7.52 (1H, d, J=2.0 Hz), 7.38(2H, d, J=8.7 Hz), 7.32 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.7 Hz), 6.82(2H, d, J=8.7 Hz), 5.09 (2H, s), 5.07 (2H, s), 3.83 (3H, s), 3.80 (3H,s), 2.54 (3H, s).

Step (3): Compound 8c→Compound 8d

Compound 8c (21.27 g, 45 mmol) was used to synthesize the targetcompound in the same way as step 3 of Example 3.

Yielded amount: 17.58 g, (96%)

¹H-NMR (DMSO-D₆) δ: 7.64 (1H, s), 7.57 (1H, s), 7.46 (2H, d, J=7.1 Hz),7.28 (2H, d, J=7.3 Hz), 6.99 (2H, d, J=7.3 Hz), 6.86 (2H, d, J=7.1 Hz),5.21 (2H, s), 5.09 (2H, s), 3.78 (3H, s), 3.74 (3H, s).

Step (4): Compound 8d→Compound 8e

Compound 8d (2.28 g, 5.0 mmol) and diisopropylethylamine (1.3 ml, 7.5mmol) were dissolved into dichloromethane (20 mL), and thereto was thenadded diphenyl chlorophosphate (1.6 ml, 7.5 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 hour. Thereto was then addedaminoethylpyrrolidine (0.7 ml, 5.5 mmol) at 0° C. The mixture wasstirred at rt for 2 hours. The reaction mixture was diluted with ethylacetate, washed with an aqueous sodium hydroxide solution, water and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The compound-containing liquid was subjected to silicagel column chromatography to elute out the desired compound withhexane/ethyl acetate (containing 3% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 8e (0.58 g, 21%).

¹H-NMR (CDCl₃) δ: 8.11 (1H, s), 8.00 (1H, s), 7.50 (1H, br s), 7.38 (2H,d, J=7.7 Hz), 7.31 (2H, d, J=7.7 Hz), 6.93 (2H, d, J=7.7 Hz), 6.82 (2H,d, J=7.7 Hz), 5.10 (4H, s), 3.83 (3H, s), 3.79 (3H, s), 3.47 (2H, t,J=6.0 Hz), 2.68 (2H, t, J=6.0 Hz), 2.55 (4H, br s), 1.79 (4H, br s).

Step (5): Compound X-1+Compound 8e→Compound 8f

Compound X-1 (932 mg, 1.00 mmol) and compound 8e (553 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 434.5 mg, (44%)

¹H-NMR (D₂O) δ: 7.73 (1H, s), 7.39 (1H, s), 7.03 (1H, s), 5.80 (1H, d,J=4.6 Hz), 5.48 (1H, d, J=4.6 Hz), 4.28 (1H, d, J=13.8 Hz), 4.14-4.08(1H, m), 3.99-3.92 (1H, m), 3.85-3.79 (1H, m), 3.74-3.69 (1H, m), 3.58(5H, br s), 2.24 (4H, br s), 1.58 (3H, d, J=6.4 Hz), 1.52 (3H, s), 1.50(3H, s).

Elem. Anal.: C32H34.8ClN7O11S2Na1.2(H2O) 5.5

Calcd.: C, 41.79; H, 5.02; Cl, 3.85; N, 10.66; S, 6.97; Na, 3.00(%).

Found: C, 41.69; H, 4.95; Cl, 3.83; N, 10.81; S, 7.10; Na, 2.96(%).

Example 9 Synthesis of Compound I-9

Step (1): Compound X-4+Compound 8e→Compound I-9

Compound X-4 (1082 mg, 1.00 mmol) and compound 8e (553 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 414.9 mg, (38%)

¹H-NMR (D₂O) δ: 7.71 (1H, d, J=2.1 Hz), 7.37 (1H, d, J=2.1 Hz), 7.08(1H, s), 5.74 (1H, d, J=4.6 Hz), 5.46 (1H, d, J=4.6 Hz), 5.09 (1H, d,J=14.2 Hz), 4.96 (1H, dd, J=9.9, 3.6 Hz), 4.27 (1H, d, J=14.2 Hz), 4.03(1H, q, J=7.0 Hz), 3.98-3.91 (1H, m), 3.85-3.45 (7H, m), 2.77-2.64 (2H,m), 2.24 (4H, br s), 1.56 (3H, d, J=7.0 Hz).

Elem. Anal.: C32H31.4ClN7O13S2Na2.6(H2O) 6.9

Calcd.: C, 38.22; H, 4.53; Cl, 3.53; N, 9.75; S, 6.38; Na, 5.94(%).

Found: C, 38.22; H, 4.53; Cl, 3.67; N, 9.84; S, 6.35; Na, 6.04(%).

Example 10 Synthesis of Compound I-10

Step (1): Compound 8d→Compound 10a

Compound 8d (2.28 g, 5.00 mmol) was used to synthesize the targetcompound in the same way as step 5 of Example 8.

Yielded amount: 0.81 g, (29%)

¹H-NMR (CDCl₃) δ: 7.55 (1H, s), 7.52 (1H, s), 7.37 (2H, d, J=7.8 Hz),7.30 (2H, d, J=7.8 Hz), 6.93 (2H, d, J=7.8 Hz), 6.82 (2H, d, J=7.8 Hz),5.10 (4H, s), 4.78-4.61 (1H, m), 3.84 (3H, s), 3.80 (3H, s), 3.58-3.43(1H, m), 3.29-2.96 (3H, m), 2.92-2.59 (1H, m), 2.28-2.12 (2H, m),1.99-1.75 (4H, m), 1.51-1.31 (1H, m).

Step (2): Compound X-1+Compound 10a→Compound I-10

Compound X-1 (932 mg, 1.00 mmol) and compound 10a (565 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 415.5 mg, (42%)

¹H-NMR (D₂O) δ: 7.58-7.56 (1H, m), 7.29 (1H, s), 7.02-7.01 (1H, m),5.83-5.81 (1H, m), 5.46-5.44 (1H, m), 5.17-5.07 (1H, m), 4.37-4.25 (2H,m), 4.08-3.48 (8H, m), 2.50-2.00 (4H, m), 1.60-1.54 (3H, m), 1.53-1.52(3H, m), 1.50-1.50 (3H, m).

Elem. Anal.: C33H34.5ClN7O11S2Na1.5(H2O) 6.4

Calcd.: C, 41.52; H, 4.99; Cl, 3.71; N, 10.27; S, 6.72; Na, 3.61(%).

Found: C, 41.32; H, 5.00; Cl, 3.42; N, 10.56; S, 6.72; Na, 3.62(%).

Example 11 Synthesis of Compound I-11

Step (1): Compound X-4+Compound 10a→Compound I-11

Compound X-4 (1082 mg, 1.00 mmol) and compound 10a (565 mg, 1.00 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 379.3 mg, (35%)

¹H-NMR (D₂O) δ: 7.58-7.56 (1H, m), 7.26 (1H, s), 7.07-7.06 (1H, m),5.78-5.76 (1H, m), 5.44-5.43 (1H, m), 5.22-5.10 (1H, m), 4.97-4.95 (1H,m), 4.39-4.27 (2H, m), 4.00-3.48 (8H, m), 2.76-2.64 (2H, m), 2.50-2.01(4H, m), 1.59-1.53 (3H, m).

Elem. Anal.: C33H31.2ClN7O13S2Na2.8(H2O) 8.2

Calcd.: C, 37.91; H, 4.59; Cl, 3.39; N, 9.38; S, 6.13; Na, 6.16(%).

Found: C, 37.92; H, 4.61; Cl, 3.41; N, 9.52; S, 6.02; Na, 6.21(%).

Example 12 Synthesis of Compound I-12

Step (1): Compound 8d→8 Compound 12a

Compound 8d (2.28 g, 5.00 mmol) was used to synthesize the targetcompound in the same way as step 4 of Example 8.

Yielded amount: 0.95 g, (33%)

¹H-NMR (CDCl₃) δ: 8.15 (1H, s), 8.08 (1H, s), 7.56 (1H, d, J=7.3 Hz),7.38 (2H, d, J=8.1 Hz), 7.31 (2H, d, J=8.1 Hz), 6.93 (2H, d, J=8.1 Hz),6.82 (2H, d, J=8.1 Hz), 5.10 (4H, s), 4.13 (1H, t, J=6.7 Hz), 3.83 (3H,s), 3.79 (3H, s), 3.19 (2H, br s), 2.30-2.17 (7H, m), 1.81-1.79 (2H, m),1.72-1.69 (2H, m).

Step (2): Compound X-1+Compound 12a→Compound 12b

Compound X-1 (745 mg, 0.80 mmol) and compound 12a (463 mg, 0.80 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 321 mg, (39%)

¹H-NMR (D₂O) δ: 7.65 (1H, d, J=2.3 Hz), 7.34 (1H, d, J=2.3 Hz), 7.03(1H, s), 5.82 (1H, d, J=4.8 Hz), 5.47 (1H, d, J=4.8 Hz), 4.31-4.27 (1H,m), 4.12-4.05 (2H, m), 3.95 (1H, br s), 3.12-3.00 (3H, m), 2.86-2.74(2H, m), 2.61-2.30 (4H, m), 2.19-2.15 (2H, m), 1.58 (3H, d, J=7.0 Hz),1.53 (3H, s), 1.51 (3H, s).

Elem. Anal.: C34H36.8ClN7O11S2Na1.2(H2O) 6.7

Calcd.: C, 42.21; H, 5.23; Cl, 3.66; N, 10.14; S, 6.63; Na, 2.85(%).

Found: C, 42.22; H, 5.26; Cl, 3.54; N, 10.28; S, 6.74; Na, 2.92(%).

Example 13 Synthesis of Compound I-13

Step (1): Compound X-4+Compound 12a→Compound I-13

Compound X-4 (829 mg, 0.80 mmol) and compound 12a (463 mg, 0.80 mmol)were used to synthesize the target compound in the same way as in step 6of Example 1.

Yielded amount: 370.4 mg, (41%)

¹H-NMR (D₂O) δ: 7.64 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz), 7.07(1H, s), 5.77 (1H, d, J=4.6 Hz), 5.45 (1H, d, J=4.6 Hz), 4.96 (1H, dd,J=9.3, 4.0 Hz), 4.31-4.27 (1H, m), 4.09-4.02 (2H, m), 3.95 (2H, br s),3.11-3.02 (3H, m), 2.86-2.65 (4H, m), 2.61-2.12 (7H, m), 1.56 (3H, d,J=7.0 Hz).

Elem. Anal.: C34H33.5ClN7O13S2Na2.5(H2O) 7.5

Calcd.: C, 39.25; H, 4.70; Cl, 3.41; N, 9.42; S, 6.16; Na, 5.52(%).

Found: C, 39.51; H, 4.83; Cl, 3.68; N, 9.30; S, 5.78; Na, 5.46(%).

Example 14 Synthesis of Compound I-14

Step (1): Compound 8d→Compound 14a

Compound 8d (2.28 g, 5.00 mmol) was used to synthesize the targetcompound in the same way as step 4 of Example 8.

Yielded amount: 0.90 g, (31%)

¹H-NMR (DMSO-D₆) δ: 8.81 (1H, t, J=5.3 Hz), 7.64 (1H, s), 7.59 (1H, s),7.45 (2H, d, J=7.1 Hz), 7.28 (2H, d, J=7.1 Hz), 6.99 (2H, d, J=7.1 Hz),6.86 (2H, d, J=7.1 Hz), 5.18 (2H, s), 5.08 (2H, s), 3.78 (3H, s), 3.74(3H, s), 3.02 (2H, d, J=5.3 Hz), 2.72 (6H, br s), 1.31 (6H, br s).

Step (2): Compound X-1+Compound 14a→Compound 14b

Compound X-1 (745 mg, 0.80 mmol) and compound 14a (450 mg, 0.78 mmol)were used to synthesize the target compound in the same way as in step 6of Example 1.

Yielded amount: 447 mg, (%)

¹H-NMR (D₂O) δ: 7.66 (1H, d, J=2.0 Hz), 7.37 (1H, d, J=2.0 Hz), 7.00(1H, s), 5.84 (1H, d, J=4.8 Hz), 5.44 (1H, d, J=4.8 Hz), 4.64 (1H, d,J=14.3 Hz), 4.08-4.05 (2H, m), 3.59-3.40 (6H, m), 3.36 (2H, s), 1.94(6H, t, J=7.6 Hz), 1.56 (3H, d, J=7.2 Hz), 1.52 (3H, s), 1.51 (3H, s).

Example 15 Synthesis of Compound I-15

Step (1): Compound X-4+Compound 14a→Compound I-15

Compound X-4 (829 mg, 0.80 mmol) and compound 14a (450 mg, 0.78 mmol)were used to synthesize the target compound in the same way as in step 6of Example 1.

Yielded amount: 388 mg

¹H-NMR (D₂O) δ: 7.67 (1H, d, J=2.3 Hz), 7.35 (1H, d, J=2.3 Hz), 7.05(1H, s), 5.80 (1H, d, J=4.8 Hz), 5.43 (1H, d, J=4.8 Hz), 4.96 (1H, dd,J=9.2, 4.1 Hz), 4.68 (1H, d, J=14.2 Hz), 4.08-3.99 (2H, m), 3.60-3.43(6H, m), 3.37 (2H, s), 2.74-2.71 (2H, m), 1.95 (6H, t, J=7.7 Hz), 1.55(3H, d, J=7.0 Hz).

Example 16 Synthesis of Compound I-16

Step (1): Compound 8d→Compound 16a

Compound 8d (2.28 g, 5.00 mmol) was used to synthesize the targetcompound in the same way as step 4 of Example 8.

Yielded amount: 0.75 g, (27%)

¹H-NMR (DMSO-D₆) δ: 7.54 (1H, s), 7.46-7.44 (3H, m), 7.29 (2H, d, J=6.3Hz), 7.00 (2H, d, J=6.3 Hz), 6.87 (2H, d, J=6.3 Hz), 5.22 (2H, s), 5.09(2H, s), 4.54 (1H, s), 3.78-3.66 (8H, m), 3.01-2.78 (6H, m), 1.99-1.62(4H, m).

Step (1): Compound X-1+Compound 16a→Compound I-16

Compound X-1 (606 mg, 0.65 mmol) and compound 16a (367 mg, 0.65 mmol)were used to synthesize the target compound in the same way as in step 6of Example 1.

Yielded amount: 213.1 mg, (33%)

¹H-NMR (D₂O) δ: 7.54 (1H, s), 7.23 (1H, s), 7.00 (1H, s), 5.87-5.84 (1H,m), 5.47-5.45 (1H, m), 4.38-4.08 (4H, m), 3.88 (2H, br s), 3.82-3.46(6H, m), 2.42-2.23 (4H, m), 1.61-1.57 (3H, m), 1.53-1.52 (3H, m),1.51-1.50 (3H, m).

Elem. Anal.: C33H34.4ClN7O11S2Na1.6(H2O) 6.7

Calcd.: C, 41.20; H, 5.01; Cl, 3.68; N, 10.19; S, 6.67; Na, 3.82(%).

Found: C, 40.92; H, 5.00; Cl, 3.48; N, 10.50; S, 6.87; Na, 3.77(%).

Example 17 Synthesis of Compound I-17

Step (1): Compound X-4+Compound 16a→Compound I-17

Compound X-4 (673 mg, 0.65 mmol) and compound 16a (367 mg, 0.65 mmol)were used to synthesize the target compound in the same way as step 6 ofExample 1.

Yielded amount: 225.6 mg, (31%)

¹H-NMR (D₂O) δ: 7.54 (1H, s), 7.23 (1H, s), 7.04 (1H, s), 5.82-5.80 (1H,m), 5.44-5.43 (1H, m), 4.98-4.94 (1H, m), 4.38-4.07 (3H, m), 3.89 (2H,br s), 3.81-3.44 (6H, m), 2.75-2.65 (2H, m), 2.46-2.24 (4H, m),1.60-1.56 (3H, m).

Elem. Anal.: C33H31ClN7O13S2Na3(H2O) 7.9

Calcd.: C, 37.95; H, 4.52; Cl, 3.39; N, 9.39; S, 6.14; Na, 6.60(%).

Found: C, 37.93; H, 4.43; Cl, 3.34; N, 9.56; S, 6.18; Na, 6.59(%).

Example 18 Synthesis of Compound I-18

Step (1): Compound 18a→Compound 18b

Compound 18a (59.1 g, 100 mmol) which was synthesized according to thesynthesis in U.S. Pat. No. 4,463,172A1 was dissolved intodichloromethane (600 ml) and thereto was then bubbled a diazomethane(170 mmol), prepared from N-methyl-N-nitroso-p-toluenesulfonamide (36.4g, 170 mmol) at 0° C. The mixture was concentrated under reducedpressure. The precipitated solid was then collected by filtration, andwashed with diisopropyl ether. In this way, compound 18b was yielded(64.98g, 103%). Compound 18b yielded was used as it was, without beingpurified, in the next reaction.

MS (m+1)=633

Step (2): Compound 18b→Compound 18c

The total amount of compound 18b yielded (64.98 g, 100 mmol) wassuspended into toluene (650 mL), and then stirred at 90° C. for 2 hours.The mixture was concentrated under reduced pressure. Thecompound-containing liquid was subjected to silica gel columnchromatography to elute out the desired compound with chloroform/ethylacetate. The desired-compound-containing fraction was concentrated underreduced pressure to yield compound 18c (23.5 g, 39%).

¹H-NMR (CDCl₃) δ: 7.41-7.29 (12H, m), 7.01-6.96 (3H, m), 6.85 (1H, d,J=10.0 Hz), 6.13 (1H, dd, J=10.0, 4.8 Hz), 4.87 (1H, d, J=12.8 Hz), 4.64(1H, d, J=4.8 Hz), 4.38 (1H, d, J=12.8 Hz), 3.84 (2H, s), 1.91-1.75 (5H,m), 1.46-1.41 (1H, m), 0.92-0.86 (1H, m).

Step (3): Compound 18c→Compound 18d

Compound 18c (23.5 g, 39 mmol) was dissolved into dimethylacetoamide(230 ml) and thereto were then added potassium iodide (38.7 g, 233 mmol)and acetyl chloride (11.10 ml, 156 mmol) in turn at 0° C. The mixturewas stirred at 0° C. for 4 hours. The reaction mixture was diluted withethyl acetate and an aqueous sodium thiosulfate solution, then separatedand washed with a saturated sodium hydrogen carbonate solution and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The compound-containing liquid was subjected to silicagel column chromatography to elute out the desired compound withhexane/ethyl acetate. The desired-compound-containing fraction wasconcentrated under reduced pressure to yield compound 18d (15.6 g, 68%).¹H-NMR (CDCl₃) δ: 7.38-7.26 (11H, m), 7.03-6.95 (3H, m), 6.25-6.19 (1H,m), 5.93-5.89 (1H, m), 5.21-5.16 (1H, m), 4.44-4.35 (2H, m), 3.86-3.82(2H, m), 1.95-1.91 (3H, m), 1.45-1.30 (3H, m),

Step (4): Compound 18d→Compound 18e

Compound 18d (15.6 g, 26.5 mmol) and anisole (5.79 mL, 53.0 mmol) weredissolved into dichloromethane (70 mL), and thereto was then addedtrifluoroacetic acid (70 mL) at 0° C. The mixture was stirred at 0° C.for 30 minutes. The reaction mixture was concentrated under reducedpressure. The precipitated solid was then collected by filtration, andwashed with diisopropyl ether to yield compound 18e (10.5 g, 94%).

¹H-NMR (DMSO-D₆) δ: 13.66 (1H, s), 9.17 (1H, d, J=8.2 Hz), 7.38-7.35(1H, m), 6.96-6.90 (2H, m), 5.81-5.78 (1H, m), 5.29-5.26 (1H, m), 4.48(2H, s), 3.74 (2H, s), 2.00 (3H, s), 1.54-1.41 (2H, m), 1.35-1.30 (1H,m), 0.95-0.90 (1H, m).

Step (5): Compound 18e→Compound 18f

Compound 18e (8.9 g, 21.1 mmol) and sodium hydrogen carbonate (2.3 g,27.4 mmol) were dissolved into boronic acid-ammonia buffer (150 mL,pH=8), and thereto was then added CAH immobilized enzyme (8.90 ml, 21.07mmol) at rt (pH was adjusted ca. 8 with 7% NH3 aq.). The mixture wasstirred at rt for 5 hours (pH was adjusted ca. 8 with 7% NH3 aq.). Thereaction mixture was diluted with acetone (300 ml), then pH was adjustedca. 3 with 2N HCl at 0° C. The reaction mixture was filtered and washedwith acetone. To the filtrate diphenyl diazomethane (9.00 g, 46.3 mmol)in Acetone (10 ml) was added at 0° C. The resulting mixture was stirredat 0° C. for 2 hr. The reaction mixture was concentrated under reducedpressure. The precipitated solid was then collected by filtration, andwashed with water and diisopropyl ether to yield compound 18f (10.19 g,89%).

¹H-NMR (CDCl₃) δ: 7.42-7.28 (11H, m), 7.01 (1H, dd, J=5.1, 3.6 Hz), 6.96(1H, d, J=3.3 Hz), 6.91 (1H, s), 6.22 (1H, d, J=8.9 Hz), 5.94 (1H, dd,J=9.0, 4.8 Hz), 5.12 (1H, d, J=4.8 Hz), 3.99 (1H, dd, J=12.8, 3.9 Hz),3.84 (2H, s), 3.27-3.21 (1H, m), 2.61 (1H, dd, J=11.2, 3.9 Hz),1.77-1.71 (1H, m), 1.39-1.31 (2H, m), 1.05-1.01 (1H, m).

Step (6): Compound 18f→Compound 18g

Compound 18f (10.2 g, 18.6 mmol) was suspended into dichloromethane (100mL), and thereto were then added 2,6-lutidine (8.7 ml, 74.6 mmol) andtriphosgene (2.8 g, 9.3 mmol) in turn at 0° C. The mixture was stirredat rt for 2 hours. The mixture was diluted with an aqueous hydrochloricacid solution and ethyl acetate, then separated and washed with asaturated sodium hydrogen carbonate and a saturated salt solution, anddried over magnesium sulfate. Magnesium sulfate was filtrated off, andthen the liquid was concentrated under reduced pressure. Thecompound-containing liquid was subjected to silica gel columnchromatography to elute out the desired compound with chloroform/ethylacetate. The desired-compound-containing fraction was concentrated underreduced pressure to yield compound 18g (5.63 g, 53%).

¹H-NMR (CDCl₃) δ: 7.42-7.26 (11H, m), 7.02-6.95 (3H, m), 6.23 (1H, d,J=8.8 Hz), 5.90 (1H, dd, J=8.8, 4.9 Hz), 5.18 (1H, d, J 4.9 Hz), 4.15(1H, d, J=11.8 Hz), 3.83 (2H, s), 3.77 (1H, d, J=11.8 Hz), 1.75-1.69(1H, m), 1.45-1.38 (2H, m), 1.04-0.98 (1H, m).

Step (7): Compound 18g→Compound 18h

Phorphorus pentachloride (2.08 g, 10 mmol) was suspended intodichloromethane (30 mL), and thereto were then added pyridine (0.89 ml,11 mmol) and compound 18g (2.83 g, 5.0 mmol) in turn at 0° C. Themixture was stirred at 0° C. for 1 hour. Thereto was then added methanol(6.1 mL, 150 mmol) at −40° C. The mixture was stirred at rt for 30minutes. The mixture was diluted with water and dichloromethane, thenseparated and washed with a saturated sodium hydrogen carbonate solutionand a saturated salt solution, and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure to yield compound 18h (2.98 g,135%). Compound 18h yielded was used as it was, without being purified,in the next reaction.

MS (m+1)=633

Step (8): Compound X-1f+Compound 18h→Compound 18i

Compound 18h and compound X-1f were dissolved into dichloromethane (25mL), and thereto were then added phenyl phosphorodichloridate (1.121 ml,7.50 mmol) and NMM (1.924 ml, 17.50 mmol) in turn at −40° C. The mixturewas stirred at −40˜−20° C. for 1 hour. The mixture was diluted with a0.2 mol/L aqueous hydrochloric acid solution and ethyl acetate, thenseparated and washed with a saturated sodium hydrogen carbonate and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The compound-containing liquid was subjected to silicagel column chromatography to elute out the desired compound withhexane/ethyl acetate. The desired-compound-containing fraction wasconcentrated under reduced pressure to yield compound 18i (2.28 g, 54%).

¹H-NMR (CDCl₃) δ: 8.23 (1H, d, J=8.7 Hz), 7.45-7.30 (13H, m), 7.00 (1H,s), 6.08 (1H, dd, J=8.7, 5.0 Hz), 5.29 (1H, d, J=5.0 Hz), 4.14 (1H, d,J=11.8 Hz), 3.81 (1H, d, J=11.8 Hz), 1.77-1.71 (1H, m), 1.53-1.37 (26H,m), 1.07-0.99 (1H, m).

Step (9): Compound 18i+Compound 18j→Compound I-18

Compound 18i (852 mg, 1.00 mmol), compound 18j (551 mg, 1.05 mmol) andsodium iodide (300 mg, 2.00 mmol) were used to synthesize the targetcompound in the same way as in step 6 of Example 1.

Yielded amount: 320.3 mg, (34%)

¹H-NMR (D₂O) δ: 6.93-6.91 (2H, m), 6.84 (1H, d, J=8.3 Hz), 5.66-5.63(2H, m), 4.30 (1H, br s), 3.90-3.63 (9H, m), 2.28-2.16 (4H, m),1.60-1.40 (9H, m), 1.22-1.17 (1H, m).

Elem. Anal.: C32H35ClN7O10S2Na (H2O) 5

Calcd.: C, 43.17; H, 5.09; Cl, 3.98; N, 11.01; S, 7.20; Na, 2.58(%).

Found: C, 43.12; H, 5.08; Cl, 4.24; N, 11.03; S, 7.08; Na, 2.47(%).

Example 19 Synthesis of Compound I-19

Step (1): Compound 18i+Compound 19a→Compound I-19

Compound 18i (852 mg, 1.00 mmol), compound 19a (542 mg, 1.05 mmol) andsodium iodide (300 mg, 2.00 mmol) were used to synthesize the targetcompound in the same way as step 6 of Example 1.

Yielded amount: 202.9 mg, (21%)

¹H-NMR (D₂O) δ: 7.12 (1H, d, J=7.5 Hz), 7.01 (1H, d, J=7.5 Hz), 6.94(1H, s), 5.74-5.66 (2H, m), 4.36 (1H, br s), 4.09 (2H, br s), 3.94-3.58(7H, m), 2.25-2.17 (4H, m), 1.63-1.43 (9H, m), 1.31-1.14 (1H, m).

Elem. Anal.: C33H34N7O11S2Na (H2O) 5.6

Calcd.: C, 44.40; H, 5.10; N, 10.98; S, 7.18; Na, 2.58(%).

Found: C, 44.40; H, 5.01; N, 11.02; S, 7.08; Na, 2.55(%).

Example 20 Synthesis of Compound I-20

Step (1): Compound 20a+Compound 20b→Compound 20c

A solution of Compound 20a (1.00 g, 2.19 mmol) in 1 dichloromethane (10mL) was cooled with ice, and thereto was added DIEA (573 μL, 3.28 mmol),and Diphenyl chlorophosphate (681 μL, 3.28 mmol). The liquid was stirredat 0° C. for 30 minutes.

A solution of Compound 20b (513 g, 2.41 mmol) in 1 dichloromethane (10mL) was cooled with ice, and thereto was added triethylamine (698 μL,5.03 mmol), and phosphate solution. After stirring at room temperaturefor 1 hour, aqueous sodium hydroxide was added to the reaction mixture,followed by extraction with ethyl acetate twice time. The combinedorganic layer was washed with water, then saturated brine, and thendried with anhydrous magnesium sulfate. The inorganic substance wasremoved by filtration, and then concentrated and subsequently dryingunder reduced pressure to yield Compound 20c as a yellow powder oil.

Yielded amount: 1.00 g (79%)

¹H-NMR (CDCl₃) δ: 1.75 (3H, d, J=14.56 Hz), 1.86 (2H, dd, J=15.31, 6.65Hz), 2.18-2.21 (2H, m), 2.28-2.30 (2H, m), 2.33 (3H, s), 3.23 (2H, s),3.80 (3H, s), 3.83 (3H, s), 4.96 (2H, s), 5.11 (2H, s), 6.83 (2H, d,J=8.53 Hz), 6.91-6.96 (3H, m), 7.33-7.36 (4H, m), 7.65 (1H, d, J=8.78Hz).

Step (2): Compound X-1+Compound 20c→Compound 20d→Compound I-20

A solution of Compound 20c (579 mg, 1.0 mmol) in dimethylformamide (2.0mL) was cooled with ice. The reaction vessel was then degassed underreduced pressure, and thereto was added Compound X-1 (932 mg, 1.0 mmol).After stirring at 0° C. for 7 hours, the reaction mixture was slowlyadded to 5% aqueous sodium chloride and sodium hydrogen sulfite cooledwith ice. The precipitated solid was collected by filtration, washedwith water, and suspended into water. The suspension was freeze-dried toyield Compound 20d as a brown solid. Compound 20d yielded was used as itwas, without being purified, in the next reaction.

The total amount of compound 20d yielded was dissolved indichloromethane (12 mL), and the solution was cooled to −40° C. Theretowere then added anisole (1.09 mL, 10 mmol) and a 2 mol/L aluminumchloride solution (5.0 mL, 10 mmol) in nitromethane in turn. The liquidwas stirred at 0° C. for 30 minutes. To the reaction liquid were addeddiisopropyl ether and a small amount of water, and the resultant wasstirred to generate a precipitate. The supernatant was removed bydecantation. To the insoluble matter adhering to the vessel were added adiluted aqueous hydrochloric acid solution, and acetonitrile. Theresultant was stirred to dissolve the matter completely. Thereto wasthen added diisopropyl ether, and the water phase was separated to becollected. The organic phase was again subjected to extraction withwater, and then all of the resultant water phases were combined witheach other. Thereto was added HP20-SS resin. Acetonitrile was thendistilled off therefrom under reduced pressure. The resultant mixedliquid was purified by ODS column chromatography. Thedesired-compound-containing fraction was concentrated under reducedpressure, and then freeze-dried to yield compound I-20 as a yellowpowder.

Yielded amount: 385 mg (43%)

¹H-NMR (D₂O) δ: 1.51 (3H, s), 1.53 (3H, s), 1.58 (3H, d, J=7.15 Hz),2.17 (2H, d, J=16.81 Hz), 2.37-2.61 (5H, m), 2.71-2.85 (2H, m), 3.10(3H, s), 3.95 (1H, s), 4.04-4.11 (3H, m), 4.24 (1H, t, J=7.53 Hz), 5.46(1H, d, J=4.89 Hz), 5.83 (1H, d, J=4.89 Hz), 6.90 (1H, d, J=8.66 Hz),7.02 (1H, s), 7.37 (1H, d, J=8.66 Hz).

MS (m+1)=820.28

Example 21 Synthesis of Compound I-21

Step (1): Compound X-2+Compound 20c→Compound I-21

From Compound X-2 (1.082 g, 1.0 mmol) and Compound 20c (579 mg, 1.0mmol), Compound I-21 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 385 mg, (43%)

¹H-NMR (D₂O) δ: 1.56 (3H, d, J=7.15 Hz), 2.18 (2H, d, J=16.81 Hz),2.27-2.83 (9H, m), 3.11 (3H, s), 3.95 (1H, s), 3.99-4.09 (3H, m), 4.24(1H, t, J=7.47 Hz), 4.97 (1H, dd, J=9.22, 4.08 Hz), 5.44 (1H, d, J=4.77Hz), 5.77 (1H, d, J=4.77 Hz), 6.87 (1H, d, J=8.66 Hz), 7.07 (1H, s),7.37 (1H, d, J=8.66 Hz).

MS (m+1)=850.27

Example 22 Synthesis of Compound I-22

Step (1): Compound X-2+Compound 22a→Compound I-22

From Compound X-2 (866 mg, 0.80 mmol) and Compound 22a (442 mg, 0.80mmol), Compound I-22 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 85 mg, (12%)

¹H-NMR (D₂O) δ: 1.56 (3H, d, J=7.03 Hz), 2.24 (4H, s), 2.65-2.77 (2H,m), 3.53-4.04 (9H, m), 4.26 (1H, d, J=14.18 Hz), 4.96 (1H, dd, J=9.60,3.58 Hz), 5.07 (1H, d, J=14.18 Hz), 5.45 (1H, d, J=4.64 Hz), 5.74 (1H,d, J=4.64 Hz), 6.87 (1H, d, J=8.66 Hz), 7.07 (1H, s), 7.34 (1H, d,J=8.66. Hz).

MS (m+1)=824.31

Example 23 Synthesis of Compound I-23

Step (1): Compound X-2+Compound 23a→Compound I-23

From Compound X-2 (1.082 g, 1.0 mmol) and Compound 23a (565 mg, 1.0mmol), Compound I-23 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 369 mg, (42%)

¹H-NMR (D₂O) δ: 1.57 (3H, dd, J=10.73, 7.09 Hz), 2.06-2.48 (4H, m),2.70-2.74 (3H, m), 3.57-4.03 (8H, m), 4.29-4.35 (2H, m), 4.95-4.98 (1H,m), 5.12-5.21 (1H, m), 5.44 (1H, d, J=4.64 Hz), 5.77 (1H, dd, J=4.64,2.13 Hz), 6.83 (1H, d, J=8.78 Hz), 7.06 (1H, d, J=2.26 Hz), 7.48 (1H, d,J=8.78 Hz).

MS (m+1)=836.19

Example 24 Synthesis of Compound I-24

Step (1): Compound X-2+Compound 24a→Compound I-24

From Compound X-2 (1.082 g, 1.0 mmol) and Compound 24a (579 mg, 1.0mmol), Compound I-24 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 442 mg, (49%)

¹H-NMR (D₂O) δ: 1.55 (3H, d, J=7.15 Hz), 1.94 (6H, t, J=7.72 Hz), 2.72(2H, t, J=5.77 Hz), 3.35 (2H, s), 3.50 (6H, dt, J=29.32, 7.75 Hz),3.98-4.08 (2H, m), 4.68 (1H, d, J=14.18 Hz), 4.96 (1H, dd, J=9.10, 4.33Hz), 5.42 (1H, d, J=4.89 Hz), 5.80 (1H, d, J=4.89 Hz), 6.90 (1H, d,J=8.53 Hz), 7.05 (1H, s), 7.31 (1H, d, J=8.53 Hz).

MS (m+1)=850.20

Example 25 Synthesis of Compound I-25

Step (1): Compound X-4+Compound 25a→Compound I-25

From Compound X-4 (1.036 g, 1.0 mmol) and Compound 25a (565 mg, 1.0mmol), Compound I-25 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 550 mg, (63%)

¹H-NMR (D₂O) δ: 1.58 (3H, dd, J=9.35, 7.22 Hz), 2.29-2.42 (4H, m),2.70-2.74 (2H, m), 3.54-3.95 (7H, m), 4.02-4.10 (1H, m), 4.22-4.38 (2H,m), 4.87 (2H, d, J=13.93 Hz), 4.95-4.98 (1H, m), 5.43 (1H, d, J=4.77Hz), 5.81 (1H, t, J=4.83 Hz), 6.83 (1H, dd, J=8.78, 6.84 Hz), 7.04 (1H,s), 7.48 (1H, d, J=8.78 Hz).

MS (m+1)=836.19

Example 26 Synthesis of Compound I-26

Step (1): Compound 26a→Compound 26b→Compound 26d

A solution of Compound 26a (1.29 g, 10 mmol) in ethanol (10 mL) wascooled with ice, and thereto was added Boc₂O solution (2.44 mL, 10.5mmol) in ethanol (10 mL) dropwise. After stirring at room temperaturefor over night, the reaction mixture was concentrated and subsequentlydrying under reduced pressure to yield Compound 26b as colorless oil.The obtained Compound 26b was used in the next reaction withoutpurification.

The total amount of Compound 26b yielded was dissolved in toluene (40mL), and the solution was cooled with ice. Thereto was added Compound26c (4.20 g, 10 mmol). After stirring at room temperature for 1 hour,then stirring at reflux for 6 hours, aqueous sodium hydroxide was addedto the reaction mixture, followed by extraction with ethyl acetate. Theinorganic substance was removed by filtration, and then concentratedunder reduced pressure. The resulting crude product was purified bysilica gel column chromatography (3% triethylamine in ethylacetate/hexane) to yield Compound 26d as a white solid.

Yielded amount: 3.60 g (57%)

¹H-NMR (CDCl₃) δ: 1.51 (4H, s), 1.56 (9H, s), 2.42-2.46 (4H, m), 2.71(2H, q, J=7.24 Hz), 3.71-3.79 (2H, m), 3.82 (6H, s), 5.18 (4H, s),6.89-6.92 (4H, m), 7.33-7.37 (6H, m).

Step (2): Compound X-1+Compound 26d→Compound I-26

From Compound X-1 (932 mg, 1.0 mmol) and Compound 26d (632 mg, 1.0mmol), Compound I-26 was obtained as a white powder using the samemethod as Example 20.

Yield: 449 mg, (57%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.51 (3H, s), 1.53 (3H, d, J=7.07 Hz),2.22 (4H, s), 3.45-3.53 (6H, m), 3.64-3.77 (2H, m), 3.97 (1H, q, J=7.07Hz), 4.26 (1H, d, J=14.31 Hz), 4.92 (1H, d, J=14.31 Hz), 5.39 (1H, d,J=4.77 Hz), 5.77 (1H, d, J=4.77 Hz), 6.98 (1H, s), 7.20 (2H, s).

MS (m+1)=773.33

Example 27 Synthesis of Compound I-27

Step (1): Compound 27a→Compound 27b

A solution of Compound 27a (911 mg, 7.0 mmol) in toluene (30 mL) wascooled with ice, and thereto was added Compound 26c (2.94 g, 7.0 mmol).After stirring at room temperature for 30 minutes, thereto was addedacetic acid (440 μL, 7.7 mmol). After stirring at reflux for 1 hour,aqueous sodium hydroxide was added to the reaction mixture, followed byextraction with ethyl acetate. The inorganic substance was removed byfiltration, and then concentrated under reduced pressure. Thereto wasadded diisopropyl ether to precipitate a solid. The solid was collectedby filtration, so as to yield compound 27b as a white solid.

Yielded amount: 2.60 g (70%)

¹H-NMR (CDCl₃) δ: 1.71-1.74 (4H, m), 2.58 (4H, s), 2.89 (2H, t, J=5.71Hz), 3.81 (6H, s), 4.29 (2H, t, J=5.71 Hz), 5.17 (4H, s), 6.90 (4H, d,J=8.66 Hz), 7.32 (2H, s), 7.34 (4H, d, J=8.66 Hz).

Step (2): Compound 1a+Compound 9a→Compound (I-9)

From Compound 1a (932 mg, 1.0 mmol) and Compound 9a (632 mg, 1.0 mmol),Compound I-9 was obtained as a white powder using the same method asExample 1.

Yield: 453 mg, (57%)

¹H-NMR (D₂O) δ: 1.51 (3H, s), 1.53 (3H, s), 1.61 (3H, d, J=7.03 Hz),2.27 (4H, s), 3.52-3.62 (2H, m), 3.71-3.78 (2H, m), 3.84-3.95 (2H, m),4.10 (1H, q, J=7.03 Hz), 4.38 (1H, d, J=14.43 Hz), 4.56-4.69 (2H, m),5.00 (1H, d, J=14.43 Hz), 5.47 (1H, d, J=4.77 Hz), 5.82 (1H, d, J=4.77Hz), 7.01 (1H, s), 7.12 (2H, s).

MS (m+1)=774.34

Example 28 Synthesis of Compound I-28

Step (1): Compound 28a→Compound 28b→Compound 28c

A solution of Compound 28a (24.4 g, 93 mmol) in dichloromethane (120 mL)was cooled with ice, and thereto was added N,O-dimethylhydroxylaminehydrochloride (16.4 g, 168 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32.2 g, 168mmol). After stirring at room temperature for 4.5 hours, water was addedto the reaction mixture, followed by extraction with dichloromethane.The organic layer was washed with saturated brine, and then dried withanhydrous magnesium sulfate. The inorganic substance was removed byfiltration, and then concentrated and subsequently drying under reducedpressure to yield Compound 28b as an orange oil. The obtained Compound28b was used in the next reaction without purification.

The total amount of Compound 28b yielded was dissolved intetrahydrofuran (500 mL), and the solution was cooled to 0° C. Theretowas added a 1 mol/L methylmagnesium bromide solution (186 mL, 186 mmol)in tetrahydrofuran. After stirring at room temperature for 5 hours,aqueous ammonium chloride was added to the reaction mixture, followed byextraction with ethyl acetate.

The organic layer was washed with water, then saturated brine, and thendried with anhydrous magnesium sulfate. The inorganic substance wasremoved by filtration, and then concentrated under reduced pressure.Thereto was added diisopropyl ether to precipitate a solid. The solidwas collected by filtration, so as to yield compound 28c.

Yielded amount: 23.5 g (97%)

¹H-NMR (CDCl₃) δ: 2.68 (3H, s), 3.90 (3H, s), 3.92 (3H, s), 7.05 (1H,s), 7.15 (1H, s).

Step (2): Compound 28c→Compound 28d

A solution of Copper bromide (7.97 g, 35.7 mmol) in ethyl acetate (20mL) was heated to reflux, and thereto was added a solution of Compound28c (5.0 g, 19.3 mmol) in chloroform (20 mL). After stirring at refluxfor 2.5 hours, the insoluble matter was removed by filtration, and thenconcentrated under reduced pressure. The resulting crude product waspurified by silica gel column chromatography (ethyl acetate/hexane) toyield Compound 28d as a yellow oil.

Yielded amount: 4.61 g (71%)

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 3.93 (3H, s), 4.59 (2H, s), 7.06 (1H,s), 7.13 (1H, s).

Step (3): Compound 28d→Compound 28e→Compound 28f

A solution of Compound 28d (4.61 g, 13.6 mmol) in methanol (180 mL) andwater (30 mL) was added hydroxylamine hydrochloride (7.58 g, 109 mmol).After stirring at room temperature for over night, aqueous hydrochloricacid was added to the reaction mixture, followed by extraction withethyl acetate. The organic layer was washed with water, then saturatedbrine, and then dried with anhydrous magnesium sulfate. The inorganicsubstance was removed by filtration, and then concentrated andsubsequently drying under reduced pressure to yield Compound 28e as ayellow oil. The obtained Compound 28e was used in the next reactionwithout purification.

The total amount of Compound 28e yielded was dissolved intetrahydrofuran (50 mL), and thereto was added pyrrolidine (3.38 mL,40.9 mmol). After stirring at room temperature for 1 hour, water wasadded to the reaction mixture, followed by extraction with ethylacetate. The organic layer was washed with water, then saturated brine,and then dried with anhydrous magnesium sulfate.

The inorganic substance was removed by filtration, and then concentratedand subsequently drying under reduced pressure to yield Compound 28f asa yellow powder.

Yielded amount: 4.63 g (99%)

¹H-NMR (CDCl₃) δ: 1.77-1.80 (4H, m), 2.64 (4H, br s), 3.49 (2H, s), 3.86(3H, s), 3.88 (3H, s), 6.68 (1H, s), 7.06 (1H, s).

Step (4): Compound 28f→Compound 28g

A solution of Compound 28f (4.29 g, 12.5 mmol) in 1,4-dioxane (300 mL)was added sodium tert-butoxide (1.80 g, 18.8 mmol). The reaction vesselwas then degassed under reduced pressure, and thereto was addedpalladium acetate (421 mg, 1.88 mmol) and 1,3-bis(diphenylphosphino)propane (1.19 mg, 2.88 mmol). After stirring at 80° C. for 4.5 hours,water was added to the reaction mixture, followed by extraction withethyl acetate twice time. The combined organic layer was washedsaturated brine, and then dried with anhydrous sodium sulfate. Theinorganic substance was removed by filtration, and then concentratedunder reduced pressure. The resulting crude product was purified bysilica gel column chromatography (ethyl acetate/hexane) to yieldCompound 28g as a yellow oil.

Yielded amount: 1.82 g (56%)

¹H-NMR (CDCl₃) δ: 1.79-1.83 (4H, m), 2.60-2.63 (4H, m), 3.94 (3H, s),3.97 (3H, s), 3.98 (2H, s), 7.02 (1H, s), 7.18 (1H, s).

Step (5): Compound 28g→Compound 28h→Compound 28i

A solution of Compound 28g (1.82 g, 6.94 mmol) in dichloromethane (20mL) was cooled with ice, and thereto was added boron tribromide (1.97mL, 20.8 mmol) dropwise. After stirring at room temperature for 1.5hour, methanol was added to the reaction mixture at 0° C., and theretowas concentrated and subsequently drying under reduced pressure to yieldCompound 28h as a brown solid. The obtained Compound 28h was used in thenext reaction without purification.

The total amount of Compound 28h yielded was suspended indichloromethane (20 mL), and the suspension was cooled with ice, andthereto was added triethylamine (1.44 mL, 10.4 mmol), DMAP (42 mg, 0.35mmol), and Boc₂O (4.83 mL, 20.8 mmol). After stirring at roomtemperature for over night, water was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedwith water, then saturated brine, and then dried with anhydrous sodiumsulfate. The inorganic substance was removed by filtration, and thenconcentrated under reduced pressure. The resulting crude product waspurified by silica gel column chromatography (3% triethylamine in ethylacetate/hexane) to yield Compound 28i as a yellow solid.

Yielded amount: 602 mg (20%)

¹H-NMR (CDCl₃) δ: 1.57 (18H, s), 1.78-1.81 (4H, m), 2.58-2.61 (4H, m),4.00 (2H, s), 7.51 (1H, s), 7.78 (1H, s).

Step (6): Compound X-1+Compound 28i→Compound I-28

From Compound X-1 (932 mg, 1.0 mmol) and Compound 28i (434 mg, 1.0mmol), Compound I-18 was obtained as a white powder using the samemethod as Example 20.

Yield: 344 mg, (47%)

¹H-NMR (D₂O) δ: 1.42 (3H, d, J=7.03 Hz), 1.48 (3H, s), 1.50 (3H, s),2.28 (4H, s), 3.52-3.65 (3H, m), 3.81-3.84 (1H, m), 4.01 (1H, q, J=7.15Hz), 4.40 (1H, d, J=14.05 Hz), 4.90 (2H, dd, J=32.12, 14.68 Hz), 5.07(1H, d, J=14.05 Hz), 5.40 (1H, d, J=4.77 Hz), 5.79 (1H, d, J=4.77 Hz),6.97 (1H, s), 7.18 (1H, s), 7.22 (1H, s).

MS (m+1)=716.06

Example 29 Synthesis of Compound I-29

Step (1): Compound 29a→Compound 29b

To a solution of Compound 29a (12.6 g, 76 mmol) in DMF (120 mL) wasadded potassium carbonate (23.0 g, 166 mmol), 4-methoxybenzylchloride(22.7 mL, 166 mmol) and sodium iodide (5.67 g, 38 mmol), and the mixturewas stirred at 70 degree for 1.5 hr. The solvent was removed byevaporation and the residue was diluted with water and ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated. The precipitated material wascollected by filtration with diisopropyl ether and dried under highvacuum to afford Compound 29b (22.7 g, 74%) as a yellowish solid.

¹H-NMR (CDCl₃) δ: 3.79 (3H, s), 3.82 (3H, s), 5.05 (2H, s), 5.17 (2H,s), 5.26 (2H, s), 6.82 (2H, d, J=8.5 Hz), 6.89 (2H, d, J=8.5 Hz), 7.00(1H, d, J=8.2 Hz), 7.22 (1H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 7.42(2H, d, J=8.4 Hz).

Step (2): Compound 29b→Compound 29c

To a solution of Compound 29b (22.4 g, 55 mmol) in methanol (55 mL) andtetrahydrofuran (55 mL) was added 2 mol/L sodium hydroxide (83 mL, 166mmol), and the mixture was stirred at 70 degree for 1.5 hr. Theresulting mixture was cooled to room temperature and then diluted withdiethyl ether. The aqueous layer was separated and adjusted pH at 3.0 byadding 2 mol/L hydrochloric acid. The mixture was extracted withdichloromethane. The organic layer was washed with water and brine,dried over magnesium sulfate, evaporated and dried under high vacuum toafford Compound 29c (20.5 g, 88%) as a pale pink solid.

¹H-NMR (CDCl₃) δ: 3.80 (3H, s), 3.84 (3H, s), 4.67 (2H, s), 5.11 (2H,s), 5.12 (2H, s), 6.82 (2H, d, J=8.7 Hz), 6.95 (2H, d, J=8.7 Hz),7.19-7.24 (4H, m), 7.39 (2H, d, J=8.7 Hz).

Step (3): Compound 29c→Compound 29d→Compound 29e

To a solution of Compound 29c (45.7 g, 108 mmol) in tetrahydrofuran (350mL) was added a solution of diphenyldiazomethane (23.0 g, 118 mmol) intetrahydrofuran (100 mL) over 20 min at room temperature. The mixturewas stirred at room temperature over night and then the solvent wasremoved by evaporation. The residue was dried under high vacuum to givea crude material containing 13e as a major product which was used forthe next step without further purification.

To a solution of Compound 29d prepared above in dichloromethane (640 mL)with stirring at 0 degree was added Dess-Martin periodinane (50.4 g, 119mmol) and then the mixture was stirred at 0 degree for 2 hr. The mixturewas diluted with water and the organic solvent was removed byevaporation. The resulting aqueous mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried overmagnesium sulfate, filtered and concentrated. The residue was trituratedwith diisopropyl ether and the solid was collected by filtration anddried under high vacuum to afford Compound 29e (51.1 g, 80%) was acolorless solid.

¹H-NMR (CDCl₃) δ: 3.79 (3H, s), 3.84 (3H, s), 4.86 (2H, s), 5.14 (2H,s), 6.68 (2H, d, J=8.66 Hz), 6.93 (2H, d, J=8.78 Hz), 6.97 (2H, d,J=8.66 Hz), 7.14 (1H, d, J=8.41 Hz), 7.19 (1H, s), 7.25-7.27 (5H, m),7.36-7.38 (7H, m), 7.61 (1H, d, J=8.41 Hz), 9.74 (1H, s).

Step (4): Compound 29e→Compound 29f

To a solution of Compound 29e (51.1 g, 87 mmol) in 1,4-dioxane (600 mL)and water (200 mL) was added amidosulfuric acid (16.9 g, 174 mmol) andsodium chlorite (19.6 g, 174 mmol). The mixture was stirred at 0 degreefor 30 min before an aqueous solution of sodium bisulfite (36.2 g, 348mmol) was added. The mixture was extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated. The solid precipitated by addingdiisopropyl ether was collected by filtration and dried under highvacuum to afford Compound 29f (51.4 g, 98%) as a colorless solid.

¹H-NMR (DMSO-D₆) δ: 3.73 (3H, s), 3.77 (3H, s), 4.71 (2H, s), 5.20 (2H,s), 6.69 (2H, d, J=8.59 Hz), 6.85 (2H, d, J=8.59 Hz), 6.97-6.99 (3H, m),7.26-7.28 (6H, m), 7.36-7.38 (5H, m), 7.45 (2H, d, J=8.59 Hz), 7.75 (1H,d, J=8.84 Hz).

Step (5): Compound 29f→Compound 29g

To a solution of Compound 29f (9.07 g, 15 mmol) in DMF (90 mL) withstirring at 0 degree was added 1-hydroxybenzotriazole (2.23 g, 16.5mmol), 1-(2-aminoethyl)pyrrolidine (2.26 mL, 18 mmol) and EDChydrochloride (3.74 g, 19.5 mmol) and then the mixture was stirred atroom temperature for 3.5 hr. The organic solvent was removed byevaporation, and the residue was diluted with water. The mixture wasextracted with ethyl acetate. The organic layer was washed with 1 mol/Lsodium hydroxide, water and brien, and then dried over magnesiumsulfate, filtered and concentrated. The precipitated material wascollected by filtration and dried under high vacuum to afford Compound29g (6.73 g, 87%) as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.74-1.77 (4H, m), 2.57-2.60 (4H, m), 2.73 (2H, t,J=6.96 Hz), 3.78-3.81 (5H, m), 3.83 (3H, s), 5.09 (2H, s), 5.28 (2H, s),6.82 (2H, d, J=8.66 Hz), 6.92 (2H, d, J=8.66 Hz), 7.12 (1H, d, J=8.03Hz), 7.31 (2H, d, J=8.66 Hz), 7.38 (2H, d, J=8.66 Hz), 7.47 (1H, d,J=8.03 Hz).

Step (6): Compound 29g→Compound 29h

A solution of Compound 29g (1.55 g, 3.0 mmol) in acetic acid (60 mL) wasadded zinc powder (3.92 g, 60 mmol). After stirring at 80° C. for 3hours, the insoluble matter was removed by filtration, and then waterwas added to the filtrate, followed by extraction with ethyl acetate.The organic layer was washed with aqueous sodium hydroxide, thensaturated brine, and then dried with anhydrous magnesium sulfate. Theinorganic substance was removed by filtration, and then concentratedunder reduced pressure. The resulting crude product was purified bysilica gel column chromatography (3% triethylamine in ethylacetate/hexane) to yield Compound 29h as a colorless oil.

Yield: 870 mg, (58%)

¹H-NMR (CDCl₃) δ: 1.74-1.78 (4H, m), 2.52-2.55 (4H, m), 2.64 (2H, t,J=6.90 Hz), 3.64 (2H, t, J=6.90 Hz), 3.79 (3H, s), 3.83 (3H, s), 4.09(2H, s), 5.04 (2H, s), 5.14 (2H, s), 6.81 (2H, d, J=6.65 Hz), 6.93 (2H,d, J=8.66 Hz), 7.09 (1H, d, J=8.28 Hz), 7.20 (2H, d, J=8.66 Hz), 7.40(2H, d, J=8.53 Hz), 7.50 (1H, d, J=8.28 Hz).

Step (7): Compound X-1+Compound 29h→Compound I-29

From Compound X-1 (745 mg, 0.80 mmol) and Compound 29h (402 mg, 0.80mmol), Compound I-29 was obtained as a white powder using the samemethod as Example 20.

Yield: 244 mg, (40%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.57 (3H, d, J=6.06 Hz),2.22 (4H, s), 3.51-3.73 (6H, m), 4.05-4.10 (3H, m), 4.29 (1H, d, J=14.15Hz), 4.49 (2H, s), 5.04 (1H, d, J=14.15 Hz), 5.47 (1H, d, J=2.53 Hz),5.80 (1H, d, J=2.53 Hz), 7.00-7.04 (2H, m), 7.22 (1H, d, J=8.08 Hz).

MS (m+1)=744.21

Example 30 Synthesis of Compound I-30

Step (1): Compound 30a→Compound 30b

From Compound 30a (1.03 g, 2.0 mmol), Compound 30b was obtained as awhite solid using the same method as Example 29.

Yield: 585 mg, (58%)

¹H-NMR (CDCl₃) δ: 1.76 (4H, s), 2.56 (4H, s), 2.72 (2H, t, J=6.32 Hz),3.70 (2H, t, J=6.32 Hz), 3.81 (6H, s), 4.34 (2H, s), 5.12 (4H, s), 6.89(4H, d, J=8.59 Hz), 6.93 (1H, s), 7.33-7.38 (5H, m).

Step (2): Compound X-1+Compound 30b→Compound I-30

From Compound X-1 (745 mg, 0.80 mmol) and Compound 30b (402 mg, 0.80mmol), Compound I-30 was obtained as a white powder using the samemethod as Example 20.

Yield: 236 mg, (39%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.56 (3H, d, J=6.57 Hz),2.23 (4H, s), 3.49-3.73 (6H, m), 4.02-4.10 (3H, m), 4.28 (1H, d, J=14.15Hz), 4.42 (2H, s), 5.02 (1H, d, J=14.15 Hz), 5.46 (1H, d, J=3.28 Hz),5.80 (1H, d, J=3.28 Hz), 7.01 (1H, s), 7.03 (1H, s), 7.17 (1H, s).

MS (m+1)=744.21

Example 31 Synthesis of Compound I-31

Step (1): Compound 31a→Compound 31b

A solution of Compound 31a (6.31 g, 32.5 mmol) in acetonitrile (60 mL)was added NCS (4.77 g, 35.7 mmol). After stirring at 60° C. for 1 hour,the insoluble matter was collected by filtration, so as to yieldcompound 31b.

Yield: 6.15 g, (83%)

¹H-NMR (CDCl₃) δ: 3.91 (3H, s), 4.09 (3H, s), 5.15 (2H, s), 7.16 (1H,s).

Step (2): Compound 31b→Compound 31c

A solution of Compound 31b (6.83 g, 30 mmol) in dichloromethane (60 mL)was cooled with ice, and thereto was added boron tribromide (9.43 mL,100 mmol) dropwise. After stirring at room temperature for 2 hours, thereaction mixture was poured to ice, and thereto was concentrateddichloromethane. Then the solid was collected by filtration, so as toyield compound 31c.

Yield: 5.57 g, (93%)

¹H-NMR (DMSO-D₆) δ: 5.15 (2H, s), 7.10 (1H, s).

Step (3): Compound 31c→Compound 31d

From Compound 31c (5.57 g, 27.8 mmol), Compound 31d was obtained as awhite solid using the same method as Example 29.

Yield: 8.45 g, (69%)

¹H-NMR (CDCl₃) δ: 3.79 (3H, s), 3.83 (3H, s), 5.03 (2H, s), 5.12 (2H,s), 5.24 (2H, s), 6.81 (2H, d, J=8.54 Hz), 6.91 (2H, d, J=8.54 Hz), 7.17(1H, s), 7.30 (2H, d, J=8.39 Hz), 7.37 (2H, d, J=8.54 Hz).

Step (4): Compound 31d→Compound 31e

From Compound 31d (8.45 g, 19.2 mmol), Compound 31e was obtained as awhite solid using the same method as Example 29.

Yield: 8.08 g, (92%)

¹H-NMR (DMSO-D₆) δ: 3.74 (3H, s), 3.77 (3H, s), 4.49 (2H, s), 4.85 (2H,s), 5.15 (2H, s), 6.85 (2H, d, J=8.54 Hz), 6.97 (2H, d, J=8.54 Hz), 7.23(2H, d, J=8.54 Hz), 7.30 (1H, s), 7.42 (2H, d, J=8.54 Hz).

Step (5): Compound 31e→Compound 31f

A solution of Compound 31e (8.23 g, 17.9 mmol) in dichloromethane (80mL) was cooled with ice, and thereto was added Dess-Martin Periodinane(8.37 g, 19.7 mmol). After stirring at room temperature for 30 minutes,water was added to the reaction mixture, followed by extraction withethyl acetate. The organic layer was washed with water, then saturatedbrine, and then dried with anhydrous sodium sulfate. The inorganicsubstance was removed by filtration, and then concentrated under reducedpressure. Thereto was added diisopropyl ether to precipitate a solid.The solid was collected by filtration, so as to yield compound 31f.

Yield: 6.38 g, (78%)

¹H-NMR (DMSO-D₆) δ: 3.73 (3H, s), 3.77 (3H, s), 5.06 (2H, s), 5.15 (2H,s), 6.85 (2H, d, J=8.54 Hz), 6.97 (2H, d, J=8.54 Hz), 7.30 (2H, d,J=8.54 Hz), 7.38 (2H, d, J=8.39 Hz), 7.58 (1H, s).

Step (6): Compound 31f→Compound 31g→Compound 31h

A solution of Compound 31f (6.38 g, 14.0 mmol) in tetrahydrofuran (30mL) was added drop-wise diphenyldiazomethane solution (2.98 g, 15.4mmol) in tetrahydrofuran (30 mL). After stirring at room temperature forover night, the reaction mixture was concentrated under reducedpressure. Thereto was added diisopropyl ether to precipitate a solid.The solid was collected by filtration, so as to yield compound 31g.

From Compound 31g, Compound 31h was obtained as a white solid using thesame method as Example 29.

Yield: 8.72 g, (98%)

¹H-NMR (DMSO-D₆) δ: 3.71 (3H, s), 3.77 (3H, s), 4.72 (2H, s), 5.19 (2H,s), 6.67 (2H, d, J=8.73 Hz), 6.79 (2H, d, J=8.73 Hz), 6.91 (1H, s), 6.98(2H, d, J=8.73 Hz), 7.26-7.47 (13H, m).

Step (7): Compound 31h→Compound 31i

From Compound 31h (4.16 g, 6.51 mmol), Compound 31i was obtained as awhite solid using the same method as Example 29.

Yield: 2.36 g, (66%)

¹H-NMR (CDCl₃) δ: 1.76 (4H, s), 2.58 (4H, s), 2.73 (2H, t, J=6.82 Hz),3.78-3.81 (5H, m), 3.84 (3H, s), 5.06 (2H, s), 5.22 (2H, s), 6.81 (2H,d, J=8.59 Hz), 6.93 (2H, d, J=8.59 Hz), 7.03 (1H, s), 7.30-7.35 (4H, m).

Step (8): Compound 31i→Compound 31j

From Compound 31i (1.10 g, 2.0 mmol), Compound 31j was obtained as acolorless oil using the same method as Example 29.

Yield: 381 mg, (36%)

¹H-NMR (CDCl₃) δ: 1.76 (4H, s), 2.53 (4H, s), 2.63 (2H, t, J=6.19 Hz),3.60 (2H, t, J=6.69 Hz), 3.79 (3H, s), 3.84 (3H, s), 4.00 (2H, s), 5.01(2H, s), 5.11 (2H, s), 6.81 (2H, d, J=8.34 Hz), 6.94 (2H, d, J=8.08 Hz),7.02 (1H, s), 7.17 (2H, d, J=7.33 Hz), 7.39 (2H, d, J=7.83 Hz).

Step (9): Compound X-1+Compound 31j→Compound I-31

From Compound X-1(745 mg, 0.80 mmol) and Compound 31j (430 mg, 0.80mmol), Compound I-31 was obtained as a white powder using the samemethod as Example 20.

Yield: 155 mg, (24%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.58 (3H, d, J=7.03 Hz),2.23 (4H, s), 3.49-3.64 (5H, m), 3.74-3.78 (1H, m), 4.00-4.11 (3H, m),4.27 (1H, d, J=14.18 Hz), 4.39 (2H, s), 5.05 (1H, d, J=14.18 Hz), 5.48(1H, d, J=4.77 Hz), 5.80 (1H, d, J=4.77 Hz), 6.87 (1H, s), 7.01 (1H, s).

MS (m+1)=778.23

Example 32 Synthesis of Compound I-32

Step (1): Compound 29f→Compound 32a

From Compound 29f (3.02 g, 5.0 mmol) and 1-(2-aminoethyl)piperidine (775μL, 5.5 mmol), Compound 32a was obtained as a white solid using the samemethod as Example 29.

Yield: 2.51 g, (95%)

¹H-NMR (CDCl₃) δ: 1.38-1.43 (2H, m), 1.51-1.56 (4H, m), 2.46 (4H, s),2.57 (2H, t, J=6.96 Hz), 3.76-3.79 (5H, m), 3.83 (3H, s), 5.09 (2H, s),5.28 (2H, s), 6.82 (2H, d, J=8.53 Hz), 6.92 (2H, d, J=8.53 Hz), 7.11(1H, d, J=8.16 Hz), 7.30-7.39 (4H, m), 7.47 (1H, d, J=8.16 Hz).

Step (2): Compound X-2+Compound 32a→Compound I-32

From Compound X-2 (1.082 g, 1.0 mmol) and Compound 32a (624 mg, 1.0mmol), Compound I-32 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 176 mg, (21%)

¹H-NMR (D₂O) δ: 1.59 (3H, d, J=7.03 Hz), 1.80-1.99 (6H, m), 2.69-2.73(2H, m), 3.29-3.39 (3H, m), 3.60-3.81 (3H, m), 4.05-4.09 (3H, m), 4.29(1H, d, J=13.93 Hz), 4.96 (1H, dd, J=9.66, 3.76 Hz), 5.11 (1H, d,J=13.93 Hz), 5.49 (1H, d, J=4.64 Hz), 5.78 (1H, d, J=4.64 Hz), 7.02 (1H,d, J=7.78 Hz), 7.09 (1H, s), 7.19 (1H, d, J=7.78 Hz).

MS (m+1)=801.88

Example 33 Synthesis of Compound I-33

Step (1): Compound X-2+Compound 33a→Compound I-33

From Compound X-2 (1.082 g, 1.0 mmol) and Compound 33a (539 mg, 1.0mmol), Compound I-33 was obtained as a white powder using the samemethod as Example 20.

Yield: 181 mg, (21%)

¹H-NMR (D₂O) δ: 1.57 (3H, d, J=7.03 Hz), 1.82-2.01 (5H, m), 2.68-2.72(2H, m), 3.29-3.35 (3H, m), 3.61-3.96 (5H, m), 4.03 (1H, q, J=7.03 Hz),4.23 (1H, d, J=13.93 Hz), 4.96 (1H, dd, J=9.47, 3.83 Hz), 5.05 (1H, d,J=13.93 Hz), 5.46 (1H, d, J=4.64 Hz), 5.77 (1H, d, J=4.64 Hz), 6.91 (1H,d, J=8.41 Hz), 7.00 (1H, d, J=8.41 Hz), 7.06 (1H, s).

MS (m+1)=809.98

Example 34 Synthesis of Compound I-34

Step (1): Compound X-2+Compound 29g→Compound I-34

From Compound X-2 (1.082 g, 1.0 mmol) and Compound 29g (517 mg, 1.0mmol), Compound I-34 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 414 mg, (50%)

¹H-NMR (D₂O) δ: 1.59 (3H, d, J=7.03 Hz), 2.23 (4H, s), 2.70-2.74 (2H,m), 3.53-3.71 (6H, m), 4.04-4.09 (3H, m), 4.32 (1H, d, J=14.18 Hz), 4.96(1H, dd, J=9.79, 3.64 Hz), 5.12 (1H, d, J=14.18 Hz), 5.47 (1H, d, J=4.64Hz), 5.76 (1H, d, J=4.64 Hz), 7.02 (1H, d, J=7.78 Hz), 7.08 (1H, s),7.17 (1H, d, J=7.78 Hz).

MS (m+1)=788.02

Example 35 Synthesis of Compound I-35

Step (1): Compound X-2+Compound 35a→Compound I-35

From Compound X-2 (1.082 g, 1.0 mmol) and Compound 35a (525 mg, 1.0mmol), Compound I-35 was obtained as a white powder using the samemethod as Example 20.

Yield: 441 mg, (53%)

¹H-NMR (D₂O) δ: 1.56 (3H, d, J=7.15 Hz), 2.24 (4H, s), 2.69-2.72 (2H,m), 3.47-3.96 (9H, m), 4.01 (1H, q, J=7.07 Hz), 4.27 (1H, d, J=14.18Hz), 4.96 (1H, dd, J=9.66, 3.76 Hz), 5.07 (1H, d, J=14.18 Hz), 5.44 (1H,d, J=4.64 Hz), 5.75 (1H, d, J=4.64 Hz), 6.90 (1H, d, J=8.41 Hz), 6.99(1H, d, J=8.41 Hz), 7.06 (1H, s).

MS (m+1)=795.97

Example 36 Synthesis of Compound I-36

Step (1): Compound 29f→Compound 36a

From Compound 29f (3.63 g, 6.0 mmol) and N,N-diethylethylenediamine(1.01 mL, 7.2 mmol), Compound 36a was obtained as a white solid usingthe same method as Example 29.

Yield: 1.98 g, (64%)

¹H-NMR (CDCl₃) δ: 7.47 (1H, d, J=8.03 Hz), 7.38 (2H, d, J=8.53 Hz), 7.31(2H, d, J=8.53 Hz), 7.11 (1H, d, J=8.03 Hz), 6.92 (2H, d, J=8.50 Hz),6.82 (2H, d, J=8.53 Hz), 5.28 (2H, s), 5.08 (2H, s), 3.83 (3H, s), 3.79(3H, s), 3.73 (2H, t, J=7.10 Hz), 2.69 (2H, t, J=7.09 Hz), 2.58 (4H, q,J=7.11 Hz), 1.01 (6H, t, J=7.09 Hz).

Step (2): Compound X-1+Compound 36a→Compound I-36

From Compound X-1 (559 mg, 0.60 mmol) and Compound 36a (311 mg, 0.60mmol), Compound I-36 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 110 mg, (24%)

¹H-NMR (D₂O) δ: 1.45 (6H, q, J=7.40 Hz), 1.50 (3H, s), 1.52 (3H, s),1.59 (3H, d, J=6.90 Hz), 3.45-3.52 (6H, m), 3.95-4.11 (3H, m), 4.20 (1H,d, J=14.31 Hz), 5.03 (1H, d, J=14.31 Hz), 5.48 (1H, d, J=4.64 Hz), 5.77(1H, d, J=4.64 Hz), 7.00 (1H, d, J=7.78 Hz), 7.04 (1H, s), 7.15 (1H, d,J=7.78 Hz).

MS (m+1)=760.08

Example 37 Synthesis of Compound I-37

Step (1): Compound 37a→Compound 37b

To a suspension of Compound 37a (4.29 g, 10 mmol) in dichloromethane (40ml) with stirring in ice bath was added N,N-diethylethylenediamine (1.69ml, 12 mmol), HOBt (1.62 g, 12 mmol) and EDC (2.30 g, 12 mmol), and thenthe mixture was stirred at room temperature over night. The resultingmixture was diluted with ethyl acetate and washed with a diluted aqueoussolution of sodium hydroxide, water and brine. The organic layer wasdried over magnesium sulfate, filtered and concentrated. Theprecipitated material was collected by filtration to afford Compound 37b(4.55g, 86%).

¹H-NMR (CDCl₃) δ: 7.47 (1H, d, J=8.7 Hz), 7.35-7.34 (4H, m), 7.03 (1H,br s), 6.94-6.92 (3H, m), 6.83 (2H, d, J=8.4 Hz), 5.08 (2H, s), 4.95(2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.50 (2H, q, J=5.8 Hz), 2.64 (2H,t, J=5.8 Hz), 2.55 (4H, q, J=7.1 Hz), 1.01 (6H, t, J=7.1 Hz).

Step (2): Compound X-1+Compound 37b→Compound I-37

From Compound X-1 (932 mg, 1.0 mmol) and Compound 37b (527 mg, 1.0mmol), Compound I-37 was obtained as a white powder using the samemethod as Example 20.

Yield: 320 mg, (41%)

¹H-NMR (D₂O) δ: 1.43 (6H, dd, J=10.73, 6.84 Hz), 1.49 (3H, s), 1.52 (3H,s), 1.57 (3H, d, J=7.03 Hz), 3.48 (6H, q, J=7.07 Hz), 3.74-3.95 (2H, m),3.99 (1H, q, J=6.86 Hz), 4.17 (1H, d, J=14.31 Hz), 5.00 (1H, d, J=14.31Hz), 5.45 (1H, d, J=4.64 Hz), 5.76 (1H, d, J=4.64 Hz), 6.90 (1H, d,J=8.41 Hz), 6.98 (1H, d, J=8.41 Hz), 7.03 (1H, s).

MS (m+1)=768.22

Example 38 Synthesis of Compound I-38

Step (1): Compound 29f→Compound 38a

From Compound 29f (3.02 g, 5.0 mmol), 20b (1.17 g, 5.5 mmol), and DIEA(1.92 mL, 11 mmol), Compound 38a was obtained as a colorless oil usingthe same method as Example 29.

Yield: 100 mg, (4%)

¹H-NMR (CDCl₃) δ: 1.74 (2H, dd, J=13.93, 6.27 Hz), 1.87-1.93 (2H, m),2.13-2.16 (2H, m), 2.21 (3H, s), 2.26-2.34 (2H, m), 3.24 (2H, s), 3.79(3H, s), 3.83 (3H, s), 4.55-4.65 (1H, m), 5.08 (2H, s), 5.25 (2H, s),6.81 (2H, d, J=8.53 Hz), 6.91 (2H, d, J=8.53 Hz), 7.09 (1H, d, J=8.16Hz), 7.30 (2H, d, J=8.66 Hz), 7.37 (2H, d, J=8.66 Hz), 7.42 (1H, d,J=8.16 Hz).

Step (2): Compound X-1+Compound 38a→Compound I-38

From Compound X-1 (466 mg, 0.50 mmol) and Compound 38a (271 mg, 0.50mmol), Compound I-38 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 126 mg, (31%)

¹H-NMR (D₂O) δ: 1.51 (3H, s), 1.53 (3H, s), 1.59 (3H, d, J=7.15 Hz),2.21 (2H, t, J=19.39 Hz), 2.51-2.66 (4H, m), 2.83-2.99 (2H, m), 3.12(3H, s), 4.00 (1H, s), 4.07-4.15 (3H, m), 4.75 (2H, d, J=14.68 Hz), 5.47(1H, d, J=4.89 Hz), 5.84 (1H, d, J=4.89 Hz), 7.02 (1H, s), 7.04 (1H, d,J=7.78 Hz), 7.17 (1H, d, J=7.78 Hz).

MS (m+1)=786.06

Example 39 Synthesis of Compound I-39

Step (1): Compound 29f→Compound 39b

From Compound 29f (3.02 g, 5.0 mmol) and Compound 39a (771 mg, 5.5mmol), Compound 39b was obtained as a white solid using the same methodas Example 29.

¹H-NMR (CDCl₃) δ: 1.41 (6H, t, J=7.65 Hz), 2.85 (6H, t, J=7.65 Hz), 3.79(3H, s), 3.83 (3H, s), 5.11 (2H, s), 5.28 (2H, s), 6.81 (2H, d, J=8.66Hz), 6.92 (2H, d, J=8.66 Hz), 7.14 (1H, d, J=8.03 Hz), 7.33 (2H, d,J=8.66 Hz), 7.37 (2H, d, J=8.66 Hz), 7.48 (1H, d, J=8.03 Hz).

Step (2): Compound 39b+Compound X-2→Compound 39c

Compound 39b (543 mg, 1.0 mmol) was added to a solution of compound X-2(932 mg, 1.0 mmol) in dimethylformamide (2 mL) at 0° C., and theresultant solution was stirred at 0° C. for 1 hour. The reaction mixturewas slowly added to a 5% salt solution (30 ml) (containing 1.5 g ofsodium bisulfite) at 0° C. The precipitated solid was collected byfiltration, washed with water, and then suspended into water. Thesuspension was freeze-dried to yield compound 39c as an orange solid.Compound 39c yielded was used as it was, without being purified, in thenext reaction.

Step (3): Compound 39c→Compound I-39

The total amount of compound 39c yielded was dissolved indichloromethane (10 mL), and the solution was cooled to −40° C. Theretowere then added anisole (1.1 mL, 10 mmol) and a 2 M aluminum chloridesolution (5.00 mL, 10 mmol) in nitromethane in turn. The resultant wasstirred at 00° C. for 30 minutes. The reaction mixture was dissolved inwater, a 2 mol/L aqueous hydrochloric acid solution, and acetonitrile.The resultant solution was then washed with diisopropyl ether. To thewater phase was added HP20-SS resin, and then acetonitrile was distilledoff under reduced pressure. The resultant mixed liquid was purified byODS column chromatography. To the resultant target-compound solution wasadded HP20-SS resin, and then acetonitrile was distilled off underreduced pressure. The resultant mixed liquid was purified by HP20-SScolumn chromatography. To the resultant target-compound solution wasadded a 0.2 N aqueous sodium hydroxide solution until the whole gave apH of 6.0. Thereafter, a piece of dry ice was added thereto. Theresultant solution was concentrated under reduced pressure, and thenfreeze-dried to yield compound I-39 as an orange powder.

Yielded amount: 168 mg (20%).

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.55 (3H, d, J=7.15 Hz),1.93 (6H, t, J=7.72 Hz), 3.41-3.53 (8H, m), 4.03-4.10 (2H, m), 4.61 (1H,d, J=14.43 Hz), 5.43 (1H, d, J=4.89 Hz), 5.84 (1H, d, J=4.89 Hz), 6.99(1H, s), 7.04 (1H, d, J=7.91 Hz), 7.17 (1H, d, J=7.91 Hz).

MS (m+1)=784.06

Example 40 Synthesis of Compound I-40

Step (1): Compound X-1+Compound 40a→Compound I-40

From Compound X-1 (932 mg, 1.0 mmol) and Compound 40a (543 mg, 1.0mmol), Compound I-40 was obtained as a white powder using the samemethod as Example 20.

Yield: 523 mg, (64%)

¹H-NMR (D₂O) δ: 1.51 (3H, s), 1.53 (3H, s), 1.56 (3H, d, J=7.15 Hz),1.96 (6H, t, J=7.59 Hz), 3.35 (2H, s), 3.45-3.57 (6H, m), 4.05-4.09 (2H,m), 4.64 (1H, d, J=14.31 Hz), 5.45 (1H, d, J=4.89 Hz), 5.85 (1H, d,J=4.89 Hz), 6.90 (1H, d, J=8.41 Hz), 6.95 (1H, d, J=8.41 Hz), 7.00 (1H,s).

MS (m+1)=792.01

Example 41 Synthesis of Compound I-41

Step (1): Compound X-1+Compound 41a→Compound I-41

From Compound X-1 (932 mg, 1.0 mmol) and Compound 41a (537 mg, 1.0mmol), Compound I-41 was obtained as a white powder using the samemethod as Example 20.

Yield: 443 mg, (55%)

¹H-NMR (D₂O) δ: 1.50 (3H, d, J=1.63 Hz), 1.52 (3H, d, J=1.88 Hz), 1.57(3H, dd, J=17.69, 6.90 Hz), 2.02-2.46 (4H, m), 3.46-4.08 (9H, m),4.25-4.53 (2H, m), 5.11 (1H, dd, J=19.89, 15.00 Hz), 5.45 (1H, d, J=4.64Hz), 5.83 (1H, d, J=4.64 Hz), 6.83-6.88 (1H, m), 6.95-6.98 (1H, m), 7.01(1H, s).

MS (m+1)=778.04

Example 42 Synthesis of Compound I-42

Step (1): Compound X-1+Compound 32a→Compound I-42

From Compound X-1 (932 mg, 1.0 mmol) and Compound 32a (624 mg, 1.0mmol), Compound I-42 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 192 mg, (24%)

¹H-NMR (D₂O) δ: 1.51 (3H, s), 1.53 (3H, s), 1.61 (3H, d, J=7.03 Hz),1.81-2.00 (6H, m), 3.28-3.39 (3H, m), 3.59-3.80 (3H, m), 4.02-4.07 (2H,m), 4.16 (1H, q, J=7.03 Hz), 4.29 (1H, d, J=14.05 Hz), 5.07 (1H, d,J=14.05 Hz), 5.50 (1H, d, J=4.77 Hz), 5.83 (1H, d, J=4.77 Hz), 7.02-7.04(2H, m), 7.17 (1H, d, J=7.78 Hz).

MS (m+1)=772.07

Example 43 Synthesis of Compound I-43

Step (1): Compound X-1+Compound 33a→Compound I-43

From Compound X-1 (932 mg, 1.0 mmol) and Compound 33a (539 mg, 1.0mmol), Compound I-43 was obtained as a white powder using the samemethod as Example 20.

Yield: 272 mg, (29%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.59 (3H, d, J=7.03 Hz),1.82-2.01 (6H, m), 3.28-3.36 (3H, m), 3.62 (1H, d, J=11.92 Hz),3.69-3.82 (3H, m), 3.89-3.96 (1H, m), 4.11 (1H, q, J=7.03 Hz), 4.23 (1H,d, J=14.18 Hz), 5.00 (1H, d, J=14.18 Hz), 5.48 (1H, d, J=4.77 Hz), 5.83(1H, d, J=4.77 Hz), 6.87 (1H, d, J=8.28 Hz), 6.95 (1H, d, J=8.28 Hz),7.02 (1H, s).

Example 44 Synthesis of Compound I-44

Step (1): Compound X-1h+Compound 44b→Compound 44c→Compound I-44

A solution of Compound 44b (404 mg, 0.80 mmol) in dimethylacetamide (2.0mL) was cooled with ice, and thereto was added Compound X-1h (672 mg,0.80 mmol). The reaction vessel was then degassed under reducedpressure, and thereto was added sodium iodide (240 mg, 1.6 mmol). Afterstirring at 15° C. for 7 hours, the reaction mixture was slowly added to5% aqueous sodium chloride and sodium hydrogen sulfite cooled with ice.The precipitated solid was collected by filtration, washed with water,and suspended into water. The suspension was freeze-dried to yieldCompound 44c as a brown solid. Compound 44c yielded was used as it was,without being purified, in the next reaction.

From Compound 44c, Compound I-44 was obtained as a white powder usingthe same method as Example 20.

Yield: 359 mg, (58%)

¹H-NMR (D₂O) δ: 1.44 (3H, s), 1.45 (3H, s), 1.61 (3H, d, J=6.78 Hz),3.49 (1H, q, J=6.78 Hz), 5.12 (1H, d, J=14.68 Hz), 5.43-5.46 (2H, m),5.92 (1H, d, J=4.39 Hz), 6.87 (1H, d, J=8.41 Hz), 6.90 (1H, s), 7.12(1H, d, J=8.41 Hz), 8.09 (2H, d, J=6.53 Hz), 8.76 (2H, d, J=6.53 Hz).

MS (m+1)=745.97

Example 45 Synthesis of Compound I-45

Step (1): Compound X-1h+Compound 45a→Compound I-45

From Compound X-1h (672 mg, 0.80 mmol) and Compound 45a (300 mg, 1.0mmol), Compound I-45 was obtained as a white powder using the samemethod as Example 44.

Yield: 332 mg, (61%)

¹H-NMR (D₂O) δ: 1.39 (3H, d, J=7.15 Hz), 1.47 (6H, s), 2.69 (3H, s),3.46 (1H, q, J=6.94 Hz), 5.22 (1H, d, J=15.31 Hz), 5.33 (1H, d, J=15.31Hz), 5.47 (1H, d, J=4.89 Hz), 5.91 (1H, d, J=4.89 Hz), 6.88 (1H, s),6.90 (1H, s), 7.29 (1H, s), 7.54 (1H, s), 8.83 (1H, s).

MS (m+1)=657.01

Example 46 Synthesis of Compound I-46

Step (1): Compound X-1h+Compound 46a→Compound I-46

From Compound X-1h (672 mg, 0.80 mmol) and Compound 46a (289 mg, 1.0mmol), Compound I-46 was obtained as a white powder using the samemethod as Example 44.

Yield: 356 mg, (67%)

¹H-NMR (D₂O) δ: 1.43 (3H, s), 1.45 (3H, s), 1.57 (3H, d, J=7.15 Hz),3.40 (1H, q, J=7.15 Hz), 5.12 (1H, d, J=14.68 Hz), 5.43-5.47 (2H, m),5.88 (1H, d, J=4.77 Hz), 6.79 (1H, s), 7.06 (1H, s), 7.36 (1H, s), 7.72(1H, d, J=6.90 Hz), 8.11 (1H, d, J=6.90 Hz), 9.01 (1H, s).

MS (m+1)=643.01

Example 47 Synthesis of Compound I-47

Step (1): Compound X-1g+Compound 44b→Compound I-47

From Compound X-1g (672 mg, 0.80 mmol) and Compound 44b (404 mg, 0.80mmol), Compound I-47 was obtained as a white powder using the samemethod as Example 44.

Yield: 367 mg, (60%)

¹H-NMR (D₂O) δ: 1.27 (3H, d, J=7.16 Hz), 1.45 (3H, s), 1.48 (3H, s),3.95 (1H, q, J=7.16 Hz), 5.28 (1H, d, J=15.16 Hz), 5.35-5.39 (2H, m),5.74 (1H, d, J=4.80 Hz), 6.88 (1H, s), 6.91 (1H, d, J=8.34 Hz), 7.15(1H, d, J=8.34 Hz), 8.19 (2H, d, J=7.33 Hz), 8.76 (2H, d, J=7.33 Hz).

MS (m+1)=745.93

Example 48 Synthesis of Compound I-48

Step (1): Compound X-1g+Compound 48a→Compound I-48

From Compound X-1g (672 mg, 0.80 mmol) and Compound 48a (395 mg, 0.80mmol), Compound I-48 was obtained as a white powder using the samemethod as Example 44.

Yield: 320 mg, (53%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.56 (3H, d, J=7.15 Hz),4.11 (1H, q, J=7.15 Hz), 4.17 (1H, d, J=13.80 Hz), 4.75 (1H, d, J=13.80Hz), 5.30 (1H, d, J=4.64 Hz), 5.73 (1H, d, J=4.64 Hz), 7.00-7.02 (2H,m), 7.08 (1H, d, J=8.78 Hz), 7.91 (2H, d, J=6.90 Hz), 8.52 (2H, d,J=6.90 Hz).

MS (m+1)=734.92

Example 49 Synthesis of Compound I-49

Step (1): Compound X-1g+Compound 45a→Compound I-49

From Compound X-1g(672 mg, 0.80 mmol) and Compound 45a (300 mg, 1.0mmol), Compound I-49 was obtained as a white powder using the samemethod as Example 44.

Yield: 244 mg, (45%)

¹H-NMR (D₂O) δ: 1.25 (3H, d, J=7.15 Hz), 1.50 (3H, s), 1.51 (3H, s),2.71 (3H, s), 3.95 (1H, q, J=7.15 Hz), 5.22 (1H, d, J=15.69 Hz), 5.44(1H, d, J=15.69 Hz), 5.51 (1H, d, J=4.77 Hz), 5.80 (1H, d, J=4.77 Hz),6.97-6.98 (2H, m), 7.34 (1H, s), 7.58 (1H, s), 8.83 (1H, s).

MS (m+1)=657.01

Example 50 Synthesis of Compound I-50

Step (1): Compound X-1g+Compound 46a→Compound I-50

From Compound X-1g (672 mg, 0.80 mmol) and Compound 46a (289 mg, 1.0mmol), Compound I-50 was obtained as a white powder using the samemethod as Example 44.

Yield: 294 mg, (55%)

¹H-NMR (D₂O) δ: 1.35 (3H, d, J=7.33 Hz), 1.49 (3H, s), 1.51 (3H, s),3.89 (1H, q, J=7.33 Hz), 5.30 (1H, d, J=14.91 Hz), 5.43 (1H, d, J=4.80Hz), 5.46 (1H, d, J=14.91 Hz), 5.82 (1H, d, J=4.80 Hz), 6.98 (1H, s),7.10 (1H, s), 7.41 (1H, s), 7.76 (1H, d, J=6.82 Hz), 8.00 (1H, d, J=6.82Hz), 8.91 (1H, s).

MS (m+1)=643.01

Example 51 Synthesis of Compound I-51

Step (1): Compound X-1+Compound 29g→Compound I-51

From Compound X-1 (932 mg, 1.0 mmol) and Compound 29g (517 mg, 1.0mmol), Compound I-51 was obtained as a yellow powder using the samemethod as Example 20.

Yield: 222 mg, (29%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.53 (3H, s), 1.60 (3H, d, J=7.03 Hz),2.23 (4H, s), 3.52-3.71 (6H, m), 3.99-4.16 (3H, m), 4.32 (1H, d, J=14.18Hz), 5.07 (1H, d, J=14.18 Hz), 5.48 (1H, d, J=4.77 Hz), 5.81 (1H, d,J=4.77 Hz), 7.00-7.02 (2H, m), 7.15 (1H, d, J=7.78 Hz).

MS (m+1)=758.25

Example 52 Synthesis of Compound I-52

Step (1): Compound X-22+Compound 35a→Compound 52b→Compound I-52

A solution of Compound X-22 (420 mg, 0.80 mmol) in dimethylacetoamide(2.0 mL) was cooled with ice, and thereto was added compound 35a (685mg, 0.80 mmol). The reaction vessel was then degassed under reducedpressure. Thereto was added sodium iodide (240 mg, 1.6 mmol), and thesolution was stirred at 15° C. for 6 hours. Dimethylformamide (5.0 mL)was added thereto, and the solution was cooled to −40° C. Thereto wasadded phosphorus tribromide (151 μL, 1.6 mmol). The solution was stirredat 0° C. for 30 minutes. The reaction mixture was slowly added to a 5%salt solution cooled with ice. The precipitated solid was collected byfiltration, washed with water, and suspended into water. The suspensionwas freeze-dried to yield compound 52b as a brown solid. Compound 52byielded was used as it was, without being purified, in the nextreaction.

From Compound 52b, Compound I-52 was obtained as a white powder usingthe same method as Example 20.

Yield: 269 mg, (43%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.58 (3H, d, J=7.02 Hz),2.23 (4H, s), 3.55-3.59 (2H, m), 3.73-3.88 (5H, m), 4.04-4.10 (1H, m),4.22-4.29 (2H, m), 5.02 (1H, d, J=13.88 Hz), 5.45 (1H, d, J=5.03 Hz),5.73 (1H, d, J=5.03 Hz), 6.88-6.90 (2H, m), 7.00 (1H, s).

MS (m+1)=766.62

Example 53 Synthesis of Compound I-53

Step (1): Compound X-23+Compound 35a→Compound I-53

From Compound X-23 (514 mg, 0.60 mmol) and Compound 35a (315 mg, 0.60mmol), Compound I-53 was obtained as a white powder using the samemethod as Example 52.

Yield: 198 mg, (42%)

¹H-NMR (D₂O) δ: 1.48 (6H, s), 1.64 (3H, d, J=6.86 Hz), 2.23 (4H, s),3.55-3.59 (2H, m), 3.73-3.88 (6H, m), 4.22-4.29 (2H, m), 4.50 (1H, d,J=14.03 Hz), 5.47 (1H, d, J=5.03 Hz), 5.79 (1H, d, J=5.03 Hz), 6.82 (1H,d, J=8.39 Hz), 6.89 (1H, s), 6.98 (1H, d, J=8.39 Hz).

MS (m+1)=766.36

Example 54 Synthesis of Compound I-54

Step (1): Compound X-22+Compound 54a→Compound I-54

From Compound X-22 (685 mg, 0.80 mmol) and Compound 54a (441 mg, 0.80mmol), Compound I-54 was obtained as a white powder using the samemethod as Example 51.

Yield: 164 mg, (25%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.62 (3H, d, J=7.02 Hz),2.17 (2H, dd, J=16.01, 6.86 Hz), 2.36-2.79 (7H, m), 3.14 (3H, s), 3.80(1H, q, J=6.66 Hz), 4.01 (1H, s), 4.10-4.23 (3H, m), 5.43 (1H, d, J=4.88Hz), 5.91 (1H, d, J=4.88 Hz), 6.89 (1H, d, J=8.39 Hz), 6.94 (1H, d,J=8.39 Hz), 6.98 (1H, s).

MS (m+1)=792.62

Example 55 Synthesis of Compound I-55

Step (1): Compound X-23+Compound 54a→Compound I-55

From Compound X-23 (514 mg, 0.60 mmol) and Compound 54a (331 mg, 0.60mmol), Compound I-55 was obtained as a white powder using the samemethod as Example 51.

Yield: 30 mg, (6%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.62 (3H, d, J=7.02 Hz),2.17 (2H, dd, J=16.01, 6.86 Hz), 2.36-2.79 (7H, m), 3.14 (3H, s), 3.80(1H, q, J=6.66 Hz), 4.01 (1H, s), 4.10-4.23 (3H, m), 5.43 (1H, d, J=4.88Hz), 5.91 (1H, d, J=4.88 Hz), 6.89 (1H, d, J=8.39 Hz), 6.94 (1H, d,J=8.39 Hz), 6.98 (1H, s).

MS (m+1)=792.44

Example 56 Synthesis of Compound I-56

Step (1): Compound 56a→Compound 56c

To a solution of Compound 56a (10.19g, 24.0 mmol) in dichloromethane(100 mL) was added Compound 56b (9.62g, 48.0 mmol), and then the mixturewas stirred at room temperature over night. The solvent was removed byevaporation and to the residue was added water and ethyl acetate. Theorganic layer separated was washed with water and brine, and then driedover MgSO4, filtered and concentrated. The residue was purified bycolumn chromatography on silica gel eluted with n-hexane/ethyl acetateto afford Compound 56c (4.45g, 39%) as an oil substance.

¹H-NMR (CDCl₃) δ: 1.55 (9H, s), 2.54 (1H, t, J=6.65 Hz), 3.80 (3H, s),3.83 (3H, s), 4.52 (2H, d, J=6.65 Hz), 5.00 (2H, s), 5.05 (2H, s), 6.81(2H, d, J=8.66 Hz), 6.90 (2H, d, J=8.66 Hz), 7.00 (1H, d, J=8.28 Hz),7.08 (1H, d, J=8.28 Hz), 7.29 (2H, d, J=8.53 Hz), 7.35 (2H, d, J=8.53Hz).

Step (2): Compound 56c→Compound 56d

To a solution of Compound 56c (4.45 g, 9.26 mmol) in dichloromethane (45mL) was added Dess-Martin periodinane (4.32 g, 10.19 mmol) at 0 degree,and then the mixture was stirred at room temperature over night. To theresulting mixture was added water. The organic solvent was removed byevaporation and the aqueous residue was extracted with ethyl acetate.The organic layer was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated. The residue was purified by columnchromatography on silica gel eluted with n-hexane/ethyl acetate toafford Compound 56d (2.91 g, 66%) as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.56 (9H, s), 3.80 (3H, s), 3.84 (3H, s), 4.97 (2H,s), 5.14 (2H, s), 6.80 (2H, d, J=8.08 Hz), 6.93 (2H, d, J=8.34 Hz), 7.10(1H, d, J=8.34 Hz), 7.26-7.28 (2H, m), 7.37 (2H, d, J=8.34 Hz), 7.60(1H, d, J=8.34 Hz), 9.88 (1H, s).

Step (3): Compound 56d→Compound 56e

To a solution of Compound 56d (2.91 g, 6.08 mmol) in 1,4-dioxane (30 mL)and water (10 mL) with stirring in ice bath was added amidosulfuric acid(1.18 g, 12.16 mmol) and sodium chlorite (1.38 g, 12.16 mmol), and thenthe mixture was stirred at 0 degree for 30 min. To the resulting mixturewas added sodium bisulfate (2.53 g, 24.32 mmol). The mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over magnesium sulfate, filtered, and concentrated. Theresidue was triturated with diisopropyl ether and the solid wascollected by filtration and dried under high vacuum to afford Compound56e (2.79 g, 93%) as a colorless solid.

¹H-NMR (DMSO-D₆) δ: 1.45 (9H, s), 3.74 (3H, s), 3.78 (3H, s), 4.84 (2H,s), 5.19 (2H, s), 6.83 (2H, d, J=8.66 Hz), 6.98 (2H, d, J=8.78 Hz), 7.20(2H, d, J=8.66 Hz), 7.31 (1H, d, J=8.78 Hz), 7.46 (2H, d, J=8.66 Hz),7.69 (1H, d, J=8.66 Hz).

Step (4): Compound 56e→Compound 56f

To a solution of Compound 56e (989 mg, 2.0 mmol) in dimethylformamide (3mL) was added 1-hydroxybenzotriazole (324 mg, 2.4 mmol),1-(2-aminoethyl)pyrrolidine (0.30 mL, 2.4 mmol) and EDC hydrochloride(460 mg, 2.4 mmol) at 0 degree. The mixture was stirred at roomtemperature for 4.5 hr. To the resulting mixture was added ice water andextracted with ethyl acetate. The organic layer was washed with 1 mol/Lsodium hydroxide solution, water and brine, and then dried overmagnesium sulfate, filtered, evaporated at 25 degree. The residue wasdried under high vacuum to afford Compound 56f (1.16g, 98%) as ayellowish oil.

¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 1.79 (4H, br s), 2.58 (4H, br s), 2.70(2H, t, J=5.81 Hz), 3.52 (2H, q, J=5.56 Hz), 3.79 (3H, s), 3.83 (3H, s),4.97 (2H, s), 5.07 (2H, s), 6.80 (2H, d, J=8.34 Hz), 6.91 (2H, d, J=8.34Hz), 6.96 (1H, d, J=8.59 Hz), 7.29 (2H, d, J=8.34 Hz), 7.33-7.36 (3H,m).

Step (5): Compound X-22+Compound 56f→Compound I-56

From Compound X-22 (475 mg, 0.59 mmol) and Compound 56f (346 mg, 0.59mmol), Compound I-56 was obtained as a white powder using the samemethod as Example 52.

Yield: 51 mg, (11%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.59 (3H, d, J=7.03 Hz),2.24 (4H, s), 3.35-3.87 (8H, m), 4.11 (1H, q, J=7.03 Hz), 4.28 (1H, d,J=14.31 Hz), 5.00 (1H, d, J=14.31 Hz), 5.48 (1H, d, J=4.77 Hz), 5.82(1H, d, J=4.77 Hz), 6.74 (1H, d, J=8.16 Hz), 6.96 (1H, d, J=8.16 Hz),7.03 (1H, s).

MS (m+1)=776.03

Example 57 Synthesis of Compound I-57

Step (1): Compound X-23+Compound 56f→Compound I-57

From Compound X-23 (685 mg, 0.80 mmol) and Compound 56f (473 mg, 0.80mmol), Compound I-57 was obtained as a white powder using the samemethod as Example 52.

Yield: 52 mg, (8%)

¹H-NMR (D₂O) δ: 1.50 (6H, s), 1.65 (3H, d, J=6.82 Hz), 2.22 (4H, s),3.58-3.87 (9H, m), 4.31 (1H, d, J=14.40 Hz), 4.46 (1H, d, J=14.40 Hz),5.48 (1H, d, J=4.80 Hz), 5.83 (1H, d, J=4.80 Hz), 6.68 (1H, d, J=8.08Hz), 6.93 (1H, d, J=8.08 Hz), 6.96 (1H, s).

MS (m+1)=776.06

Example 58 Synthesis of Compound I-58

Step (1): Compound X-23+Compound 29g→Compound I-58)

From Compound X-23 (685 mg, 0.80 mmol) and Compound 29g (413 mg, 0.80mmol), Compound I-58 was obtained as a yellow powder using the samemethod as Example 52.

Yield: 46 mg, (7%)

¹H-NMR (D₂O) δ: 1.46 (3H, s), 1.47 (3H, s), 1.68 (3H, d, J=6.78 Hz),2.21 (4H, s), 3.49-3.55 (1H, m), 3.74-3.93 (6H, m), 4.02-4.05 (2H, m),4.27 (1H, d, J=14.43 Hz), 4.55 (1H, d, J=13.93 Hz), 5.52 (1H, d, J=4.77Hz), 5.87 (1H, d, J=4.77 Hz), 6.91 (1H, s), 6.96 (1H, s), 7.04 (1H, d,J=7.53 Hz).

MS (m+1)=758.03

The compounds shown below were obtained from Compound X-1g and the eachcorresponding amine in the same way as example 39.

Example 59 Synthesis of Compound I-59

Yielded amount: 423 g (52%)

¹H-NMR (D₂O) δ: 6.93-6.91 (1H, m), 6.93-6.91 (1H, m), 6.81-6.77 (1H, m),5.86-5.83 (1H, m), 5.47-5.44 (1H, m), 4.13-3.98 (4H, m), 3.69-3.63 (2H,m), 3.49-2.95 (7H, m), 1.59-1.56 (3H, m), 1.52 (3H, s), 1.50 (3H, s).

[M+H]=778.23

Example 60 Synthesis of Compound I-60

Yielded amount: 516 g (62%)

¹H-NMR (D₂O) δ: 7.39 (1H, s), 7.19 (1H, s), 7.01 (1H, s), 5.84 (1H, d,J=5.0 Hz), 5.45 (1H, d, J=5.0 Hz), 4.63 (1H, d, J=14.9 Hz), 4.09-4.04(2H, m), 3.55-3.43 (6H, m), 3.35 (2H, br s), 1.93 (6H, t, J=7.8 Hz),1.56 (3H, d, J=7.3 Hz), 1.52 (3H, s), 1.50 (3H, s).

[M+H]=792.27

Example 61 Synthesis of Compound I-61

Yielded amount: 346 mg (42%)

¹H-NMR (D₂O) δ: 7.39 (1H, s), 7.23 (1H, s), 7.01 (1H, s), 5.80 (1H, d,J=4.8 Hz), 5.45 (1H, d, J=4.8 Hz), 5.03 (1H, d, J=14.3 Hz), 4.25 (1H, d,J=14.3 Hz), 4.09-4.04 (1H, m), 3.92-3.85 (1H, m), 3.79-3.70 (2H, m),3.60-3.44 (5H, m), 2.29-2.15 (4H, m), 1.57 (3H, d, J=7.0 Hz), 1.52 (3H,s), 1.50 (3H, s). [M+H]=766.24

Example 62 Synthesis of Compound I-62

Yielded amount: 396 mg (48%)

¹H-NMR (D₂O) δ: 7.02-7.00 (1H, m), 6.92 (1H, d, J=8.3 Hz), 6.81-6.77(1H, m), 5.86-5.83 (1H, m), 5.47-5.44 (1H, m), 4.13-3.98 (5H, m),3.69-2.95 (11H, m), 1.58 (3H, t, J=6.6 Hz), 1.52 (3H, s), 1.50 (3H, s).[M+H]=778.20

Example 63 Synthesis of Compound I-63

Yielded amount: 405 mg (50%)

¹H-NMR (D₂O) δ: 7.14 (1H, br s), 7.02-6.98 (2H, br m), 5.85-5.81 (1H,m), 5.45 (1H, d, J=4.9 Hz), 4.14-3.67 (8H, m), 3.42-2.95 (8H, m),1.58-1.55 (3H, m), 1.52 (3H, br s), 1.50 (3H, br s). [M+H]=778.20

Example 64 Synthesis of Compound I-64

Yielded amount: 279 mg (35%)

¹H-NMR (D₂O) δ: 7.11 (1H, s), 7.02 (1H, s), 6.94 (1H, s), 5.83 (1H, d,J=4.8 Hz), 5.46 (1H, d, J=4.8 Hz), 5.12 (1H, d, J=14.3 Hz), 4.28 (1H, d,J=14.3 Hz), 4.07-3.55 (8H, m), 2.21-2.00 (4H, br m), 1.58 (3H, d, J=6.8Hz), 1.53 (3H, s), 1.51 (3H, s). [M+H]=778.20

Example 65 Synthesis of Compound I-65

Yielded amount: 406 mg (50%)

¹H-NMR (D₂O) δ: 7.08-7.04 (1H, m), 6.99 (1H, br s), 6.93 (1H, br s),5.89-5.84 (1H, br m), 5.47-5.44 (1H, br m), 4.31-3.47 (11H, m),2.37-2.23 (4H, br m), 1.57 (3H, d, J=6.5 Hz), 1.52 (3H, br s), 1.50 (3H,br s).

[M+H]=778.23

Example 66 Synthesis of Compound I-66

Yielded amount: 272 mg (33%)

¹H-NMR (D₂O) δ: 7.32 (1H, d, J=2.0 Hz), 7.17 (1H, s), 7.02 (1H, s), 5.82(1H, d, J=4.8 Hz), 5.46 (1H, d, J=4.8 Hz), 4.21-3.94 (5H, m), 3.11 (3H,br s), 2.81-2.32 (7H, m), 2.19 (2H, d, J=17.2 Hz), 1.58 (3H, d, J=7.0Hz), 1.53 (3H, s), 1.51 (3H, s). [M+H]=792.24

Example 67 Synthesis of Compound I-67

Yielded amount: 321 mg (40%)

¹H-NMR (D₂O) δ: 7.00 (1H, s), 6.89-6.81 (2H, m), 5.85 (1H, d, J=4.6 Hz),5.45 (1H, d, J=4.6 Hz), 4.37-4.27 (1H, m), 4.11-4.03 (3H, m), 3.85-3.62(7H, m), 2.35 (4H, br s), 1.58 (3H, d, J=6.0 Hz), 1.52 (3H, s), 1.50(3H, s).

[M+H]=762.32

Example 68 Synthesis of Compound I-68

Yielded amount: 319 mg (40%)

¹H-NMR (D₂O) δ: 7.01 (1H, s), 6.92-6.89 (1H, br m), 6.84 (1H, s), 5.83(1H, d, J=4.9 Hz), 5.46 (1H, d, J=4.9 Hz), 5.12 (1H, d, J=14.4 Hz),4.30-3.52 (10H, m), 2.21-2.02 (4H, br m), 1.58 (3H, d, J=7.0 Hz), 1.53(3H, s), 1.50 (3H, s).

[M+H]=762.32

Example 69 Synthesis of Compound I-69

Yielded amount: 369 mg (47%)

¹H-NMR (D₂O) δ: 7.01 (1H, d, J=6.1 Hz), 6.95-6.92 (1H, m), 6.88 (1H, brs), 5.85-5.81 (1H, m), 5.45 (1H, d, J=4.9 Hz), 4.14-2.94 (16H, m), 1.57(3H, d, J=7.0 Hz), 1.52 (3H, s), 1.50 (3H, s). [M+H]=762.50

Example 70 Synthesis of Compound I-70

Yielded amount: 300 mg (37%)

¹H-NMR (D₂O) δ: 7.19-7.15 (2H, m), 7.01 (1H, s), 5.81 (1H, d, J=4.8 Hz),5.46 (1H, d, J=4.8 Hz), 5.03 (1H, d, J=14.3 Hz), 4.25 (1H, d, J=14.3Hz), 4.07 (1H, q, J=7.1 Hz), 3.92-3.86 (1H, m), 3.81-3.71 (2H, m),3.62-3.44 (5H, m), 2.27-2.17 (4H, m), 1.57 (3H, d, J=7.2 Hz), 1.52 (3H,s), 1.50 (3H, s). [M+H]=750.47

Example 71 Synthesis of Compound I-71

Yielded amount: 143 mg (17%)

¹H-NMR (D₂O) δ: 7.14-7.09 (2H, m), 7.02 (1H, s), 5.83 (1H, d, J=4.8 Hz),5.47 (1H, d, J=4.8 Hz), 4.20 (1H, t, J=7.2 Hz), 4.13-4.05 (3H, m), 3.95(1H, br s), 3.11 (3H, s), 2.81-2.41 (7H, m), 2.19 (2H, d, J=16.9 Hz),1.58 (3H, d, J=7.0 Hz), 1.53 (3H, s), 1.51 (3H, s).

[M+H]=776.25

Example 72 Synthesis of Compound I-72

Yielded amount: 486 mg (60%)

¹H-NMR (D₂O) δ: 7.18-7.13 (2H, m), 7.00 (1H, s), 5.84 (1H, d, J=4.8 Hz),5.44 (1H, d, J=4.8 Hz), 4.64 (1H, d, J=14.6 Hz), 4.07 (2H, dd, J=14.6,8.2 Hz), 3.57-3.40 (6H, m), 3.35 (2H, s), 1.93 (6H, t, J=7.7 Hz), 1.56(3H, d, J=7.2 Hz), 1.52 (3H, s), 1.50 (3H, s).

[M+H]=776.22

Example 73 Synthesis of Compound I-73

Yielded amount: 379 mg (45%)

¹H-NMR (D₂O) δ: 7.16 (2H, br s), 6.99 (1H, s), 5.83 (1H, d, J=4.8 Hz),5.42 (1H, d, J=4.8 Hz), 4.62 (1H, d, J=14.4 Hz), 4.08-4.02 (2H, m),3.52-3.40 (8H, m), 1.92 (6H, t, J=7.7 Hz), 1.54 (3H, d, J=7.2 Hz), 1.52(3H, s), 1.50 (3H, s).

[M+H]=784.32

Example 74 Synthesis of Compound I-74

Yielded amount: 203 mg (23%)

¹H-NMR (D₂O) δ: 7.33 (1H, d, J=8.7 Hz), 7.02 (1H, d, J=2.4 Hz), 6.89(1H, d, J=8.7 Hz), 5.80 (1H, d, J=4.8 Hz), 5.47 (1H, d, J=4.8 Hz), 5.03(1H, d, J=14.3 Hz), 4.26 (1H, d, J=14.3 Hz), 4.07 (1H, q, J=7.1 Hz),3.97-3.90 (1H, m), 3.84-3.77 (1H, m), 3.70-3.48 (6H, m), 2.27-2.18 (4H,br m), 1.57 (3H, d, J=7.0 Hz), 1.52 (3H, s), 1.50 (3H, s).

[M+H]=794.36

Example 75 Synthesis of Compound I-75

Yielded amount: 410 mg (45%)

¹H-NMR (D₂O) δ: 7.47 (1H, d, J=8.4 Hz), 7.00 (1H, br s), 6.81 (1H, brs), 5.86-5.83 (1H, br m), 5.46 (1H, br s), 4.86-4.83 (1H, br m),4.38-4.31 (1H, m), 4.24 (1H, br s), 4.10-3.52 (8H, m), 2.41-2.27 (4H, brm), 1.60-1.56 (3H, m), 1.52 (3H, br s), 1.45 (3H, br s).

[M+H]=806.35

Example 76 Synthesis of Compound I-76

Yielded amount: 424 mg (48%)

¹H-NMR (D₂O) δ: 7.47 (1H, d, J=8.7 Hz), 7.02 (1H, s), 6.84 (1H, d, J=8.7Hz), 5.82-5.81 (1H, br m), 5.46-5.45 (1H, br m), 5.17-5.08 (1H, m),4.33-4.23 (2H, m), 4.07-3.56 (9H, m), 2.48-2.06 (4H, m), 1.60-1.55 (3H,m), 1.53 (3H, s), 1.51 (3H, s).

[M+H]=806.35

Example 77 Synthesis of Compound I-77

Yielded amount: 102 mg (12%)

¹H-NMR (D₂O) δ: 7.19 (2H, s), 7.02 (1H, s), 5.83 (1H, d, J=4.8 Hz), 5.47(1H, d, J=4.8 Hz), 4.14-4.06 (3H, m), 3.99 (1H, br s), 3.12 (3H, s),2.98-2.14 (10H, m), 1.59 (3H, d, J=7.2 Hz), 1.53 (3H, s), 1.51 (3H, s).

[M+H]=784.39

Example 78 Synthesis of Compound I-78

Compound X-5 (543 mg, 1.0 mmol) and Compound X-2b (1.3 g, 1.0 mmol) wereused to synthesize the target compound I-78 in the same way as Example39.

Yielded amount: 231 mg (25%)

¹H-NMR (D₂O) δ: 7.22 (2H, s), 7.03 (1H, s), 5.78 (1H, d, J=4.8 Hz), 5.41(1H, d, J=4.8 Hz), 4.96 (1H, dd, J=9.1, 4.2 Hz), 4.67 (1H, t, J=12.9Hz), 4.06-3.98 (2H, m), 3.54-3.33 (8H, m), 2.72-2.69 (2H, m), 1.93 (6H,t, J=7.7 Hz), 1.54 (3H, d, J=7.2 Hz).

[M+H]=814.27

The compounds shown below were obtained from Compound X-2b and the eachcorresponding amine in the same way as Example 78.

Example 79 Synthesis of Compound I-79

Yielded amount: 75 mg (8%)

¹H-NMR (D₂O) δ: 7.27 (2H, s), 7.08 (1H, s), 5.75 (1H, d, J=4.6 Hz), 5.46(1H, d, J=4.6 Hz), 5.12 (1H, d, J=14.2 Hz), 4.96 (1H, dd, J=9.6, 3.8Hz), 4.31 (1H, d, J=14.2 Hz), 4.13-4.02 (3H, m), 3.69-3.51 (6H, m),2.77-2.65 (2H, m), 2.22-2.07 (4H, m), 1.58 (3H, d, J=7.0 Hz).

[M+H]=788.24

Example 80 Synthesis of Compound I-80

Yielded amount: 59 mg (5%)

¹H-NMR (D₂O) δ: 7.24 (2H, s), 7.07 (1H, s), 5.77 (1H, d, J=4.8 Hz), 5.45(1H, d, J=4.8 Hz), 4.97 (2H, dd, J=9.2, 3.9 Hz), 4.10-3.99 (4H, m), 3.13(3H, s), 3.03-2.46 (9H, m), 2.28-2.12 (2H, m), 1.58 (3H, d, J=7.2 Hz).

[M+H]=814.20

Example 81 Synthesis of Compound I-81

Yielded amount: 427 mg (49%)

¹H-NMR (D₂O) δ: 7.44-7.41 (1H, m), 7.33 (1H, s), 7.01 (1H, s), 5.84 (1H,d, J=4.8 Hz), 5.45 (1H, d, J=4.8 Hz), 4.65 (1H, d, J=14.3 Hz), 4.07 (2H,t, J=6.9 Hz), 3.59-3.42 (6H, m), 3.37 (2H, s), 1.95 (6H, t, J=7.6 Hz),1.56 (3H, d, J=7.0 Hz), 1.52 (3H, s), 1.51 (3H, s).

[M+H]=804.3

Example 82 Synthesis of Compound I-82

Yielded amount: 325 mg (51%)

¹H-NMR (D₂O) δ: 7.33-7.29 (1H, m), 7.22 (1H, br s), 7.00 (1H, br s),5.85 (1H, t, J=5.5 Hz), 5.45 (1H, t, J=4.6 Hz), 4.38-4.27 (1H, m),4.19-4.07 (2H, m), 3.88-3.49 (7H, m), 2.43-2.27 (4H, m), 1.61-1.56 (3H,m), 1.52 (3H, d, J=2.5 Hz), 1.50 (3H, d, J=1.9 Hz).

[M+H]=790.26

Example 83 Synthesis of Compound I-83

Yielded amount: 333 mg (40%)

¹H-NMR (D₂O) δ: 7.44-7.41 (1H, m), 7.34 (1H, s), 7.02 (1H, s), 5.82 (1H,d, J=4.9 Hz), 5.46 (1H, d, J=4.9 Hz), 4.29 (1H, t, J=7.4 Hz), 4.12-4.04(3H, m), 3.95 (1H, br s), 3.11 (3H, s), 2.87-2.72 (2H, m), 2.55-2.32(4H, m), 2.17 (2H, d, J=16.8 Hz), 1.58 (3H, d, J=7.0 Hz), 1.53 (3H, s),1.51 (3H, s).

[M+H]=804.3

Example 84 Synthesis of Compound I-84

Yielded amount: 307 mg (38%)

¹H-NMR (D₂O) δ: 7.51-7.48 (1H, m), 7.40 (1H, s), 7.02 (1H, s), 5.80 (1H,d, J=4.8 Hz), 5.47 (1H, d, J=4.8 Hz), 5.04 (1H, d, J=14.3 Hz), 4.27 (1H,d, J=14.3 Hz), 4.09 (1H, dd, J=13.9, 6.8 Hz), 3.97-3.38 (8H, m), 2.23(4H, dd, J=12.4, 7.5 Hz), 1.58 (3H, d, J=7.0 Hz), 1.52 (3H, s), 1.50(3H, s).

[M+H]=778.27

Example 85 Synthesis of Compound I-85

Yielded amount: 395 mg (49%)

¹H-NMR (D₂O) δ: 7.37-7.33 (1H, m), 7.25 (1H, s), 7.02-7.00 (1H, br m),5.83-5.81 (1H, br m), 5.45 (1H, d, J=4.9 Hz), 5.13 (1H, dd, J=22.5, 14.3Hz), 4.39-4.26 (2H, m), 4.09-3.52 (9H, m), 2.26-2.04 (4H, m), 1.60-1.54(3H, br m), 1.52-1.52 (3H, br m), 1.50 (3H, br s).

[M+H]=790.26

Example 86 Synthesis of Compound I-86

Step (1): Compound X-1+Compound 86a→Compound I-86

Compound X-1 (932 mg, 1.0 mmol) was added to a solution of compound 86a(564 mg, 1.00 mmol) in dimethylformamide (2 mL) at 0° C., and theresultant solution was stirred at 0° C. for 5 hours. The reactionmixture was slowly added to a 5% salt solution (30 ml) (containing 1.5 gof sodium bisulfite) at 0° C. The precipitated solid was collected byfiltration, washed with water, and then suspended into water. Thesuspension was freeze-dried to yield compound 86b as an orange solid.Compound 86b yielded was used as it was, without being purified, in thenext reaction.

The total amount of compound 86b yielded was dissolved indichloromethane (10 mL), and the solution was cooled to −40° C. Theretowere then added anisole (1.1 mL, 10 mmol) and a 2 mol/L aluminumchloride solution (5.00 mL, 10 mmol) in nitromethane in turn. Theresultant was stirred at 0° C. for 30 minutes. The reaction mixture wasdissolved in water, a 2 mol/L aqueous hydrochloric acid solution, andacetonitrile. The resultant solution was then washed with diisopropylether. To the water phase was added HP20-SS resin, and then acetonitrilewas distilled off under reduced pressure. The resultant mixed liquid waspurified by ODS column chromatography. To the resultant target-compoundsolution was added HP20-SS resin, and then acetonitrile was distilledoff under reduced pressure. The resultant mixed liquid was purified byHP20-SS column chromatography. To the resultant target-compound solutionwas added a 0.2 N aqueous sodium hydroxide solution until the whole gavea pH of 6.0. Thereafter, a piece of dry ice was added thereto. Theresultant solution was concentrated under reduced pressure, and thenfreeze-dried to yield compound I-86 as a yellow powder.

Yielded amount: 472 mg (53%).

¹H-NMR (D₂O) δ: 7.00 (1H, s), 6.80 (1H, s), 5.82 (1H, d, J=4.8 Hz), 5.49(1H, d, J=4.8 Hz), 4.99 (1H, d, J=14.3 Hz), 4.56 (2H, br s), 4.41-4.39(3H, br m), 4.14 (1H, br s), 3.73 (1H, br s), 3.52-3.50 (3H, br m), 2.24(4H, br s), 1.55-1.44 (12H, m).

[M+H]=805.4

Example 87 Synthesis of Compound I-87

Step (1): Compound X-1+Compound 87a→Compound I-87

Compound X-1 (932 mg, 1.0 mmol) and compound 87a (541 mg, 1.0 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 298 mg (35%)

¹H-NMR (D₂O) δ: 8.24 (1H, s), 7.48 (2H, d, J=7.3 Hz), 6.98 (1H, s), 5.82(1H, d, J=4.9 Hz), 5.48 (1H, d, J=4.9 Hz), 4.89 (1H, d, J=14.3 Hz),4.46-4.38 (2H, br m), 4.23 (1H, d, J=14.3 Hz), 4.16-4.10 (1H, br m),3.59 (2H, br s), 3.36 (3H, br s), 2.22 (4H, d, J=7.2 Hz), 1.55-1.47 (9H,m), 1.44 (1H, d, J=5.6 Hz), 1.33-1.32 (2H, br m), 1.11 (2H, br s).

[M+H]=782.42

Example 88 Synthesis of Compound I-88

Step (1): Compound X-1+Compound 88a→Compound I-88

Compound X-1 (533 mg, 0.57 mmol) and compound 88a (329 mg, 0.57 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount: 136 mg (27%)

¹H-NMR (D₂O) δ: 8.19 (1H, s), 7.41 (1H, s), 7.00 (1H, s), 5.83 (1H, d,J=4.9 Hz), 5.49 (1H, d, J=4.9 Hz), 4.89 (1H, d, J=14.2 Hz), 4.39 (2H,s), 4.22 (1H, d, J=14.2 Hz), 4.13 (1H, d, J=7.0 Hz), 3.56 (2H, s), 3.36(3H, s), 2.21 (4H, s), 1.55-1.51 (9H, m), 1.32 (2H, s), 1.07 (2H, s).

[M+H]=816.21

Example 89 Synthesis of Compound I-89

Step (1): Compound X-1+Compound 89a→Compound I-89

Compound X-1 (932 mg, 1 mmol) and compound 89a (620 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 135 mg (14%)

¹H-NMR (D₂O) δ: 8.45 (1H, s), 7.00 (1H, s), 6.79 (1H, s), 5.82 (1H, d,J=4.6 Hz), 5.48 (1H, d, J=4.6 Hz), 5.03 (1H, d, J=14.4 Hz), 4.33-4.21(3H, m), 4.07-3.91 (2H, m), 3.73-3.48 (6H, m), 2.24 (4H, br s), 1.57(3H, d, J=7.0 Hz), 1.51-1.49 (9H, m), 1.42 (3H, t, J=6.4 Hz).

[M+H]=782.42

Example 90 Synthesis of Compound I-90

Step (1): Compound X-1+Compound 90a→Compound I-90

Compound X-1 (932 mg, 1 mmol) and compound 90a (632 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 234 mg (25%)

¹H-NMR (D₂O) δ: 8.36 (1H, s), 7.23 (1H, s), 6.99 (1H, s), 5.83 (1H, d,J=4.6 Hz), 5.48 (1H, d, J=4.6 Hz), 5.03 (1H, d, J=14.2 Hz), 4.30 (1H, d,J=14.2 Hz), 4.06 (1H, br s), 3.90-3.36 (10H, m), 2.24 (4H, br s), 1.58(3H, d, J=6.8 Hz), 1.51 (3H, s), 1.49 (3H, s), 1.44 (1H, d, J=5.6 Hz),1.29 (2H, d, J=6.5 Hz), 1.03 (2H, br s).

[M+H]=873.35

Example 91 Synthesis of Compound I-91

Step (1): Compound X-1+Compound 91a→Compound I-91

Compound X-1 (932 mg, 1 mmol) and compound 91a (557 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 334 mg (38%)

¹H-NMR (D₂O) δ: 8.36 (1H, s), 7.68-7.65 (2H, m), 6.99 (1H, s), 5.83 (1H,d, J=4.9 Hz), 5.47 (1H, d, J=4.9 Hz), 4.90 (1H, d, J=15.2 Hz), 4.56-4.45(2H, m), 4.25 (1H, d, J=13.9 Hz), 3.59 (1H, br s), 3.39-3.36 (3H, br m),2.26-2.23 (4H, br m), 1.87 (9H, s), 1.56-1.49 (9H, m).

[M+H]=798.18.

Example 92 Synthesis of Compound I-92

Step (1): Compound 92a→Compound 92b

To a solution of 92a (4 g, 9.47 mmol) in MeOH (35 ml) was addedO-(4-methoxybenzyl)hydroxylamine (1.45 ml, 9.47 mmol) in MeOH (5 ml) at0° C. under N2. The mixture was stirred at 0° C. for 1 h. The mixturewas filtered off and the filtrate was washed IPE and Et₂O to yieldcompound 92b (3.87 g, 73%, E/Z=1:15).

Compound 92b

¹H-NMR (CDCl3) δ: 7.34-7.27 (5H, m), 7.05 (1H, dd, J=8.4, 1.6 Hz),6.94-6.84 (9H, m), 5.16 (2H, s), 5.05 (4H, s), 4.63 (1H, s), 3.81 (3H,s), 3.79 (3H, s), 3.77 (3H, s).

Step (2): Compound 92b→Compound 92c

To a solution of 92b (1.11 g, 2.00 mmol) in DMA (10 ml) was added HOBt(0.35 g, 2.60 mmol) and WSCD HCl (0.46 g, 2.40 mmol) at 0° C. Themixture was stirred at 0° C. for 1 h. The reaction mixture was addedquinuclidin-4-ylmethanamine (0.33 g, 2.40 mmol) at 0° C. and then themixture was stirred at 00° C. for overnight. The reaction mixture wasdiluted with ethyl acetate, washed with an aqueous sodium hydroxidesolution, water and a saturated salt solution, and dried over magnesiumsulfate. Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The compound-containing liquid wassubjected to silica gel column chromatography to elute out the desiredcompound with hexane/ethyl acetate (containing 10% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 92c (0.63 g, 46%, single isomer).

Compound 92c

¹H-NMR (DMSO-D₆) δ: 8.44-8.41 (1H, br m), 7.36-7.32 (6H, m), 7.24 (1H,d, J=1.8 Hz), 7.10 (1H, d, J=8.5 Hz), 6.98 (1H, dd, J=8.5, 1.8 Hz),6.94-6.91 (6H, m), 5.06 (4H, s), 5.00 (2H, s), 3.75 (9H, s), 2.92 (2H,d, J=6.3 Hz), 2.54 (6H, t, J=7.7 Hz), 1.19 (6H, t, J=7.5 Hz).

Step (3): Compound X-24+Compound 92c→Compound I-92

Compound X-24 (886 mg, 1 mmol) and compound 92c (680 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 518 mg (60%)

¹H-NMR (D₂O) δ: 7.15 (1H, d, J=1.8 Hz), 7.00-6.94 (3H, m), 5.85 (1H, d,J=4.9 Hz), 5.45 (1H, d, J=4.9 Hz), 4.63 (1H, d, J=14.3 Hz), 4.08-4.05(2H, m), 3.54-3.38 (8H, m), 1.96-1.92 (6H, m), 1.56 (3H, d, J=7.2 Hz),1.53 (3H, s), 1.51 (3H, s).

[M+H]=802.14.

Example 93 Synthesis of Compound I-93

Step (1): Compound 92a→Compound 93a

To a solution of 92a (3 g, 7.10 mmol) in MeOH (30 ml) was addedO-4-methylhydroxylammonium chloride (1.54 g, 18.46 mmol) and Et₃N (2.75ml, 19.8 mmol) at 0° C. under N2. The mixture was stirred at 0° C. for5.5 h. The mixture was concentrated under reduced pressure. The reactionmixture was diluted with ethyl acetate, washed with an aqueoushydrochloric acid, water and a saturated salt solution, and dried overmagnesium sulfate. Magnesium sulfate was filtrated off, and then theliquid was concentrated under reduced pressure to yield crude compound93a (3.21 g)

Step (2): Compound 93a→Compound 93b

To a solution of 93a (3.21 g, 7.10 mmol) in DMA (20 ml) was added HOBt(1.24 g, 9.23 mmol) and WSCD HCl (1.63 g, 8.52 mmol) at 0° C. Themixture was stirred at 0° C. for 1 h. The reaction mixture was addedquinuclidin-4-ylmethanamine (1.19 g, 8.52 mmol) at 0° C. and then themixture was stirred at 0° C. for 1 h. The reaction mixture was dilutedwith ethyl acetate, washed with an aqueous sodium hydroxide solution,water and a saturated salt solution, and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The compound-containing liquid wassubjected to silica gel column chromatography to elute out the desiredcompound with hexane/ethyl acetate (containing 10% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 93b (1.59 g, 39%, E/Z=1:4).

compound 93b

¹H-NMR (DMSO-D6) δ: 8.46-8.43 (1H, m), 7.40-7.32 (4H, m), 7.27-7.24 (1H,m), 7.13-7.11 (1H, m), 7.01 (1H, dd, J=8.4, 1.9 Hz), 6.96-6.92 (4H, m),5.07 (2H, s), 4.99 (2H, s), 3.87 (2H, s), 3.76-3.75 (6H, br m),3.01-2.97 (2H, m), 2.71-2.68 (6H, m), 1.32-1.29 (6H, m).

Step (3): Compound X-24+Compound 93b→Compound I-93

Compound X-24 (886 mg, 1 mmol) and compound 93b (680 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 518 mg (60%)

¹H-NMR (D₂O) δ: 7.17 (1H, s), 7.01-6.95 (3H, m), 5.85 (1H, d, J=4.8 Hz),5.46 (1H, d, J=4.8 Hz), 4.64 (1H, d, J=14.2 Hz), 4.09-4.06 (2H, m), 3.98(3H, s), 3.55-3.45 (6H, m), 3.38 (2H, br s), 1.95-1.91 (6H, m), 1.57(3H, d, J=7.0 Hz), 1.52 (3H, s), 1.50 (3H, s).

[M+H]=815.22.

Example 94 and 95 Synthesis of Compound I-94 and 1-95

Step (1): Compound 94a→Compound 94b

To a solution of 94a (4 g, 8.76 mmol) in MeOH (40 ml) was addedO-(4-methoxybenzyl)hydroxylamine (2.09 g, 9.63 mmol) at 0° C. under N2.The mixture was stirred at 0° C. for 1 h. The mixture was concentratedunder reduced pressure. The reaction mixture was diluted with ethylacetate, washed with an aqueous hydrochloric acid, water and a saturatedsalt solution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure to yield crude compound 94b (5.02 g, 8.76 mmol, E/Z=1:1.5)

Step (2): Compound 94b→Compound 94c and 94d

To a solution of 94b (1.77 g, 3 mmol) in DMA (10 ml) was added HOBt(0.52 g, 3.90 mmol) and WSCD HCl (0.69 g, 3.60 mmol) at 0° C. Themixture was stirred at 0° C. for 1 h. The reaction mixture was addedquinuclidin-4-ylmethanamine (0.50 g, 3.60 mmol) at 0° C. and then themixture was stirred at 0° C. for 1 h. The reaction mixture was dilutedwith ethyl acetate, washed with an aqueous sodium hydroxide solution,water and a saturated salt solution, and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The compound-containing liquid wassubjected to silica gel column chromatography to elute out the desiredcompound with hexane/ethyl acetate (containing 10% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 94c (0.88 g, 41%, E/Z=1:10) and compound 94d(0.61. 29%, E/Z=4.5:1).

Compound 94c

¹H-NMR (DMSO-D6) δ: 8.35 (1H, t, J=6.3 Hz), 7.45 (2H, d, J=7.2 Hz), 7.39(2H, d, J=8.5 Hz), 7.30 (2H, d, J=8.6 Hz), 7.25-7.18 (2H, m), 6.97 (4H,dd, J=11.7, 8.7 Hz), 6.86 (2H, d, J=31.6 Hz), 5.16 (2H, s), 5.10 (2H,s), 4.87 (2H, s), 3.78 (3H, s), 3.76 (3H, s), 3.75 (3H, s), 2.91 (2H, d,J=6.3 Hz), 2.58-2.54 (6H, m), 1.21-1.14 (6H, m).

Compound 94d

¹H-NMR (DMSO-D6) δ: 7.98 (1H, t, J=6.3 Hz), 7.43 (2H, d, J=8.2 Hz),7.31-7.24 (4H, m), 7.18 (2H, d, J=7.4 Hz), 6.98 (2H, d, J=8.5 Hz), 6.90(2H, d, J=8.5 Hz), 6.85 (2H, d, J=8.2 Hz), 5.13 (2H, s), 5.11 (2H, s),4.85 (2H, s), 3.77 (3H, s), 3.74 (6H, s), 2.96 (2H, d, J=6.3 Hz),2.73-2.70 (6H, m), 1.30-1.26 (6H, m).

Step (3): Compound X-24+Compound 94c→Compound I-94

Compound X-24 (754 mg, 0.85 mmol) and compound 94c (608 mg, 0.85 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount: 410 mg (55%)

¹H-NMR (D₂O) δ: 7.00 (1H, s), 6.97-6.90 (2H, m), 5.85 (1H, d, J=4.8 Hz),5.45 (1H, d, J=4.8 Hz), 4.62 (1H, d, J=14.3 Hz), 4.09-4.04 (2H, m),3.52-3.30 (8H, m), 1.93-1.90 (6H, m), 1.56 (3H, d, J=7.3 Hz), 1.52 (3H,s), 1.50 (3H, s).

[M+H]=835.24.

Step (4): Compound X-24+Compound 94d→Compound I-95

Compound X-24 (886 mg, 1 mmol) and compound 94d (714 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 403 mg (46%)

¹H-NMR (D₂O) δ: 7.00 (1H, s), 6.97-6.90 (1H, m), 6.78 (1H, d, J=8.3 Hz),5.85 (1H, d, J=4.8 Hz), 5.45-5.42 (1H, m), 4.64-4.59 (2H, m), 4.07-3.97(2H, m), 3.52-3.30 (8H, m), 1.94-1.87 (6H, m), 1.57-1.51 (9H, m).

[M+H]=835.21

Example 96 Synthesis of Compound I-96

Step (1): Compound 94a→Compound 96a

To a solution of 94a (6 g, 13.1 mmol) in MeOH (60 ml) was addedO-4-methylhydroxylammonium chloride (1.64 g, 19.7 mmol) and Et₃N (2.73ml, 19.7 mmol) at 0° C. under N2. The mixture was stirred at 0° C. for1.5 h. The mixture was concentrated under reduced pressure. The reactionmixture was diluted with ethyl acetate, washed with an aqueoushydrochloric acid, water and a saturated salt solution, and dried overmagnesium sulfate. Magnesium sulfate was filtrated off, and then theliquid was concentrated under reduced pressure to yield crude compound96a (6.38 g, E/Z=1:2.5)

Step (2): Compound 96a→Compound 96b

To a solution of 96a (6.38 g, 13.1 mmol) in DMA (50 ml) was added HOBt(2.3 g, 17.0 mmol) and WSCD HCl (3.02 g, 17.7 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 h. The reaction mixture was addedquinuclidin-4-ylmethanamine (2.2 g, 15.7 mmol) at 0° C. and then themixture was stirred at 0° C. for 1 h. The reaction mixture was dilutedwith ethyl acetate, washed with an aqueous sodium hydroxide solution,water and a saturated salt solution, and dried over magnesium sulfate.Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The residue was recrystallized withhexane/ethyl acetate/a little of methanol to yield compound 96b (0.56 g,7%, single isomer)

Compound 96b ¹H-NMR (DMSO-D6) δ: 8.35 (1H, t, J=6.3 Hz), 7.44 (2H, d,J=8.5 Hz), 7.29 (2H, d, J=8.5 Hz), 7.23 (1H, d, J=8.9 Hz), 7.20 (1H, d,J=8.9 Hz), 6.98 (2H, d, J=8.5 Hz), 6.86 (2H, d, J=8.5 Hz), 5.15 (2H, s),4.87 (2H, s), 3.90 (3H, s), 3.77 (3H, s), 3.74 (3H, s), 2.94 (2H, d,J=6.3 Hz), 2.71-2.67 (6H, m), 1.30-1.26 (6H, m).

Step (3): Compound X-24+Compound 96b→Compound I-96

Compound X-24 (743 mg, 0.84 mmol) and compound 96b (510 mg, 0.84 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount: 226 mg (28%)

¹H-NMR (D₂O) δ: 7.01 (1H, s), 6.97 (1H, d, J=8.4 Hz), 6.91 (1H, d, J=8.4Hz), 5.85 (1H, d, J=4.8 Hz), 5.45 (1H, d, J=4.8 Hz), 4.63 (1H, d, J=14.7Hz), 4.09-4.00 (5H, m), 3.53-3.43 (6H, m), 3.33 (2H, s), 1.92-1.88 (6H,m), 1.54 (3H, d, J=7.3 Hz), 1.52 (3H, s), 1.50 (3H, s).

[M+H]=849.25

Example 97 Synthesis of Compound I-97

Step (1): Compound X-24+Compound 97a→Compound 1-97

Compound X-24 (7.40 g, 8.37 mmol) and compound 97a (5.56 g, 8.37 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount: 1.81 g (26%)

¹H-NMR (D₂O) δ: 7.98 (1H, s), 6.97 (1H, s), 6.62 (1H, s), 5.82 (1H, d,J=4.5 Hz), 5.50 (1H, d, J=4.5 Hz), 4.90 (1H, d, J=14.4 Hz), 4.36 (2H,s), 4.21-4.12 (2H, m), 3.56 (1H, br s), 3.36 (3H, br s), 2.24-2.21 (4H,br m), 1.54 (3H, d, J=7.7 Hz), 1.51 (3H, s), 1.49 (3H, s).

[M+H]=776.18

Example 98 Synthesis of Compound I-98

Step (1): Compound 94a+→Compound 98a

To a solution of 94a (1.37 g, 3 mmol) in MeOH (6 ml) was addedtert-butyl 2-(aminooxy)acetate (0.44 g, 3 mmol) at 0° C. under N2. Themixture was stirred at rt for 1 h. The mixture was concentrated underreduced pressure. The reaction mixture was diluted with ethyl acetate,washed with an aqueous hydrochloric acid, water and a saturated saltsolution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The residue was recrystallized withdichloromethane/diisopropyl ether to yield compound 98a (0.90 g, 51%,single isomer).

Compound 98a

¹H-NMR (CDCl3) δ: 7.34 (4H, d, J=8.4 Hz), 7.23 (1H, d, J=8.5 Hz), 6.92(3H, dd, J=8.4, 5.1 Hz), 6.83 (2H, d, J=8.5 Hz), 5.08 (2H, s), 4.95 (2H,s), 4.73 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 1.51 (9H, s).

Step (2): Compound 98a→Compound 98b

Compound 98a (0.87 g, 1.49 mmol) and triethylamine (0.29 ml, 2.09 mmol)were dissolved into dimethylacetamide (6 mL), and thereto was then addedMethanesulfonyl chloride (0.15 ml, 1.94 mmol) at −20° C. The mixture wasstirred at −20° C. for 30 minutes. Thereto was then addedquinuclidin-4-ylmethanamine (0.23 g, 1.64 mmol) at 0° C. The mixture wasstirred at 0° C. for 1 h. The reaction mixture was diluted with ethylacetate, washed with an aqueous sodium hydroxide solution, water and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The compound-containing liquid was subjected to silicagel column chromatography to elute out the desired compound withhexane/ethyl acetate (containing 10% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 98b (0.72 g, 69%).

Compound 98b

¹H-NMR (DMSO-D6) δ: 8.20 (1H, t, J=6.1 Hz), 7.44 (2H, d, J=8.5 Hz), 7.29(2H, d, J=8.5 Hz), 7.24 (2H, d, J=7.5 Hz), 7.17 (2H, d, J=7.5 Hz), 6.98(2H, d, J=8.5 Hz), 6.86 (2H, d, J=8.5 Hz), 5.16 (2H, s), 4.87 (2H, s),4.69 (2H, s), 3.77 (3H, s), 3.74 (3H, s), 2.99 (2H, d, J=6.3 Hz),2.72-2.68 (6H, m), 1.45 (9H, s), 1.33-1.29 (6H, m).

Step (3): Compound X-24+Compound 98b→Compound I-98

Compound X-24 (886 mg, 1 mmol) and compound 98b (708 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 567 mg (59%)

¹H-NMR (D₂O) δ: 7.01-6.99 (2H, m), 6.94-6.91 (1H, m), 5.85 (1H, d, J=4.8Hz), 5.46 (1H, d, J=4.8 Hz), 4.65-4.62 (3H, m), 4.11-4.05 (2H, m),3.53-3.37 (9H, m), 1.95-1.91 (6H, m), 1.56 (3H, d, J=7.0 Hz), 1.52 (3H,s), 1.50 (3H, s).

[M+H]=893.23

Example 99 Synthesis of Compound I-99

Step (1): Compound 94a→Compound 99a

To a solution of tert-butyl 2-(aminooxy)-2-methylpropanoate (5.25 g, 30mmol) in MeOH (60 ml) was added 94a (9.16 g, 30 mmol) at 0° C. under N2.The mixture was stirred at rt for 1 h. The mixture was concentratedunder reduced pressure. The reaction mixture was diluted with ethylacetate, washed with an aqueous hydrochloric acid, water and a saturatedsalt solution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The residue was recrystallized withdichloromethane/diisopropyl ether to yield crude compound 99a (16 g,87%, E/Z=1:1.5).

Step (2): Compound 99a→Compound 99b

To a solution of 99a (1.6 g, 2.61 mmol) in ethyl acetate (16 ml) wasadded WSCD HCl (0.55 g, 2.87 mmol) and DMAP (0.03 g, 0.26 mmol) and2-(trimethylsilyl)ethanol (0.43 ml, 2.87 mmol) at 0° C. The mixture wasstirred at rt for 1 h. The reaction mixture was diluted with ethylacetate, washed with an aqueous hydrochloric acid, water and a saturatedsalt solution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The compound-containing liquid was subjected to silica gelcolumn chromatography to elute out the desired compound withhexane/ethyl acetate to chloroform/methanol. Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 99b (1.23 g, 66%, E/Z=1:10).

Compound 99b

¹H-NMR (CDCl3) δ: 7.36 (4H, dd, J=8.5, 3.8 Hz), 7.07 (1H, d, J=8.5 Hz),6.93 (3H, t, J=6.8 Hz), 6.83 (2H, d, J=8.5 Hz), 5.06 (2H, s), 4.97 (2H,s), 4.33 (2H, t, J=8.2 Hz), 3.84 (3H, s), 3.80 (3H, s), 1.47 (9H, s),1.03 (2H, t, J=8.2 Hz), 0.02 (9H, s).

Step (3): Compound 99b→Compound 99c

To a solution of 99b (1.42 g, 2 mmol) in THF (14 ml) was added 1M TBAFin THF (4 ml, 4 mmol) at 0° C. The mixture was stirred at rt for 1 h.The reaction mixture was diluted with ethyl acetate, washed with anaqueous hydrochloric acid, water and a saturated salt solution, anddried over magnesium sulfate. Magnesium sulfate was filtrated off, andthen the liquid was concentrated under reduced pressure to yieldcompound 99c (1.22 g).

Compound 99c

¹H-NMR (CDCl3) δ: 7.37-7.33 (4H, m), 6.97 (2H, br s), 6.93 (2H, d, J=8.6Hz), 6.83 (2H, d, J=8.6 Hz), 5.07 (2H, s), 4.99 (2H, s), 3.84 (3H, s),3.80 (3H, s), 1.50 (6H, s), 1.47 (9H, s).

Step (4): Compound 99c→Compound 99d

Compound 99c (1.22 g, 2 mmol) and triethylamine (0.38 ml, 2.80 mmol)were dissolved into dimethylacetamide (13 mL), and thereto was thenadded Methanesulfonyl chloride (0.20 ml, 2.60 mmol) at −20° C. Themixture was stirred at −20° C. for 30 minutes. Thereto was then addedquinuclidin-4-ylmethanamine (0.31 g, 2.20 mmol) at 0° C. The mixture wasstirred at 0° C. for 1 h. The reaction mixture was diluted with ethylacetate, washed with an aqueous sodium hydroxide solution, water and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The precipitated solid was then collected byfiltration, and washed with diisopropyl ether to yield compound 99d(1.01 g, 51%, E/Z=1:10).

Compound 99d

¹H-NMR (DMSO-D6) δ: 7.73 (1H, t, J=6.5 Hz), 7.45 (2H, d, J=8.2 Hz), 7.29(2H, d, J=8.2 Hz), 7.24 (1H, d, J=8.5 Hz), 7.06 (1H, d, J=8.5 Hz), 6.99(2H, d, J=8.2 Hz), 6.85 (2H, d, J=8.2 Hz), 5.15 (2H, s), 4.88 (2H, s),3.78 (3H, s), 3.74 (3H, s), 2.96 (2H, d, J=6.4 Hz), 2.71-2.68 (6H, m),1.42 (15H, s), 1.29-1.25 (6H, m).

Step (5): Compound X-24+Compound 99d→Compound I-99

Compound X-24 (901 mg, 1.02 mmol) and compound 99d (749 mg, 1.02 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount: 431 mg (45%)

¹H-NMR (D₂O) δ: 7.01 (1H, s), 6.95 (1H, d, J=8.3 Hz), 6.88 (1H, d, J=8.3Hz), 5.85 (1H, d, J=4.6 Hz), 5.46 (1H, d, J=4.6 Hz), 4.63 (1H, d, J=13.9Hz), 4.09-4.04 (2H, m), 3.52-3.37 (6H, m), 3.30 (2H, br s), 1.92-1.89(6H, m), 1.56 (3H, d, J=6.9 Hz), 1.52 (3H, s), 1.50 (3H, s), 1.44 (6H,s).

[M+H]=921.46

Example 100 Synthesis of Compound I-100

Step (1): Compound 100a+Compound 100b→Compound 100c

To a solution of 100b (28.9 g, 53 mmol) in THF (250 ml) was added 100a(6.69 g, 53 mmol) in THF (50 ml) at 0° C. The mixture was stirred at rtfor 1 h. The reaction mixture was diluted with ethyl acetate, washedwith an aqueous sodium hydroxide solution, water and a saturated saltsolution, and dried over magnesium sulfate. Magnesium sulfate wasfiltrated off, and then the liquid was concentrated under reducedpressure. The precipitated solid was then collected by filtration, andwashed with diisopropyl ether to yield compound 100c (24.1 g, 85%)

Compound 100c

¹H-NMR (DMSO-D6) δ: 8.40 (1H, t, J=6.0 Hz), 7.43 (2H, d, J=8.5 Hz), 7.33(2H, d, J=8.5 Hz), 7.19 (1H, d, J=8.7 Hz), 7.13 (1H, d, J=8.7 Hz), 6.98(2H, d, J=8.5 Hz), 6.89 (2H, d, J=8.5 Hz), 5.16 (2H, s), 4.89 (2H, s),3.78 (3H, s), 3.76 (3H, s), 3.53 (2H, d, J=6.0 Hz), 2.85-2.78 (2H, m),2.57-2.54 (2H, m), 2.25 (2H, s), 1.62-1.57 (2H, m), 1.24-1.18 (2H, m).

Step (2): Compound X-24+Compound 100c→Compound I-100

Compound X-24 (886 mg, 1 mmol) and compound 100c (537 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 500 mg (63%)

¹H-NMR (D₂O) δ: 7.01 (1H, s), 6.95 (1H, d, J=8.4 Hz), 6.89 (1H, d, J=8.4Hz), 5.82 (1H, d, J=4.8 Hz), 5.45 (1H, d, J=4.8 Hz), 4.92 (1H, d, J=14.6Hz), 4.28 (1H, d, J=14.6 Hz), 4.07-4.02 (1H, m), 3.71-3.56 (6H, m),3.44-3.42 (1H, br m), 3.35-3.33 (1H, br m), 2.24 (2H, br s), 2.01 (2H,br s), 1.57 (3H, d, J=7.2 Hz), 1.52 (3H, s), 1.50 (3H, s).

[M+H]=778.19

Example 101 Synthesis of Compound I-101

Step (1): Compound 100a+Compound 98a→Compound 101a

Compound 98a (1.17 g, 2 mmol) was used to synthesize the target compound101a in the same way as in Step (2) of Example 98.

Yielded amount: 1.15 g (82%)

Compound 101a

¹H-NMR (DMSO-D6) δ: 8.41 (1H, t, J=6.1 Hz), 7.43 (2H, d, J=8.4 Hz), 7.29(2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.9 Hz), 6.98(2H, d, J=8.5 Hz), 6.86 (2H, d, J=8.5 Hz), 5.16 (2H, s), 4.88 (2H, s),4.66 (2H, s), 3.77 (3H, s), 3.74 (3H, s), 3.54 (2H, d, J=6.0 Hz),2.79-2.73 (2H, m), 2.51-2.49 (2H, m), 2.18 (2H, s), 1.60-1.52 (2H, m),1.44 (9H, s), 1.18-1.12 (2H, m).

Step (2): Compound X-24+Compound 101a→Compound I-101

Compound X-24 (1 g, 1.14 mmol) and compound 101a (788 mg, 1.14 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount: 453 mg (43%)

¹H-NMR (D₂O) δ: 7.02-6.99 (2H, m), 6.93 (1H, d, J=8.4 Hz), 5.83 (1H, d,J=4.8 Hz), 5.47 (1H, d, J=4.8 Hz), 4.89 (1H, d, J=14.4 Hz), 4.62 (2H,s), 4.25 (1H, d, J=14.4 Hz), 3.97-3.92 (1H, m), 3.77-3.50 (6H, m), 3.37(1H, d, J=8.4 Hz), 3.24 (1H, d, J=8.4 Hz), 2.22 (2H, br s), 1.98 (2H, brs), 1.54-1.51 (9H, m).

Elem. Anal.: C35H37ClN8Na2O13S2(H2O) 8.6

Calcd.: C, 38.99; H, 5.07; N, 10.39; S, 5.95; Na, 4.26; Cl, 3.29(%).

Found: C, 38.88; H, 4.94; N, 10.53; S, 5.95; Na, 4.40; Cl, 3.57(%).

Example 102 and 103 Synthesis of Compound I-102 and I-103

Step (1): Compound 100a+Compound 94b→Compound 102a and 102b

Compound 94b (5.76 g, 9.73 mmol) and triethylamine (1.88 ml, 13.6 mmol)were dissolved into dimethylacetamide (35 mL), and thereto was thenadded Methanesulfonyl chloride (0.98 ml, 12.6 mmol) at −20° C. Themixture was stirred at −20° C. for 30 minutes. Thereto was then addedcompound 100a (1.35 g, 10.7 mmol) in DMA (5 ml) at 0° C. The mixture wasstirred at 0° C. for 1 h. The reaction mixture was diluted with ethylacetate, washed with an aqueous sodium hydroxide solution, water and asaturated salt solution, and dried over magnesium sulfate. Magnesiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The precipitated solid was then collected byfiltration, and washed with ethyl acetate to yield compound 102a (3.2 g,47%, single isomer). The residue was subjected to silica gel columnchromatography to elute out the desired compound with ethylacetate/methanol (containing 10% triethyl amine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 102b (2 g, 29%, E/Z=10:1).

Compound 102a

¹H-NMR (DMSO-D6) δ: 8.51 (1H, t, J=6.1 Hz), 7.44 (2H, d, J=8.5 Hz), 7.35(2H, d, J=8.5 Hz), 7.28 (2H, t, J=8.5 Hz), 7.23 (1H, d, J=8.8 Hz), 7.18(1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.5 Hz), 6.93 (2H, d, J=8.5 Hz), 6.86(2H, d, J=8.5 Hz), 5.15 (2H, s), 5.08 (2H, s), 4.87 (2H, s), 3.77 (3H,s), 3.76 (3H, s), 3.75 (3H, s), 3.45 (2H, d, J=6.1 Hz), 2.59-2.52 (2H,m), 2.31 (2H, br s), 2.03 (2H, br s), 1.44-1.38 (2H, m), 1.01-0.95 (2H,m).

Compound 102b

¹H-NMR (DMSO-D6) δ: 8.26 (1H, t, J=6.3 Hz), 7.43 (2H, d, J=8.5 Hz), 7.30(2H, d, J=8.5 Hz), 7.24 (2H, d, J=7.7 Hz), 7.17 (2H, d, J=7.7 Hz), 6.97(2H, d, J=8.6 Hz), 6.90 (2H, dd, J=8.6, 1.9 Hz), 6.85 (2H, d, J=8.5 Hz),5.12 (2H, s), 5.11 (2H, s), 4.86 (2H, s), 3.77 (3H, s), 3.74 (6H, s),3.50 (2H, d, J=6.3 Hz), 2.76-2.72 (2H, m), 2.43-2.40 (2H, m), 1.54-1.48(2H, m), 1.19-1.11 (2H, m).

Step (2): Compound X-24+Compound 102a→Compound I-102

Compound X-24 (886 mg, 1 mmol) and compound 102a (700 mg, 1 mmol) wereused to synthesize the target compound in the same way as E

Yielded amount: 432 mg (51%)

¹H-NMR (D₂O) δ: 7.02 (1H, s), 6.94 (2H, dd, J=14.4, 8.3 Hz), 5.82 (1H,d, J=4.9 Hz), 5.46 (1H, d, J=4.9 Hz), 4.90 (1H, d, J=14.6 Hz), 4.24 (1H,d, J=14.6 Hz), 3.96-3.91 (1H, m), 3.75-3.51 (6H, m), 3.36 (1H, d, J=8.4Hz), 3.23 (1H, d, J=8.4 Hz), 2.20 (2H, s), 1.96 (2H, s), 1.54-1.51 (9H,m).

Elem. Anal.: C33H36ClN8NaO11S2(H2O) 6.7

Calcd.: C, 41.12; H, 5.17; N, 11.62; S, 6.65; Na, 2.38; Cl, 3.68(%).

Found: C, 41.02; H, 5.10; N, 11.69; S, 6.67; Na, 2.52; Cl, 3.83(%).

Step (3): Compound X-24+Compound 102b→Compound I-103

Compound X-24 (886 mg, 1 mmol) and compound 102b (700 mg, 1 mmol) wereused to synthesize the target compound in the same way as Example 86.

Yielded amount: 365 mg (43%)

¹H-NMR (D₂O) δ: 7.02 (1H, s), 6.96 (1H, d, J=12.3 Hz), 6.80 (1H, d,J=8.4 Hz), 5.82 (1H, d, J=4.8 Hz), 5.48 (1H, d, J=4.8 Hz), 4.89 (1H, d,J=14.6 Hz), 4.24 (1H, d, J=14.6 Hz), 3.99-3.92 (1H, m), 3.75-3.52 (6H,m), 3.34 (1H, d, J=8.5 Hz), 3.22 (1H, d, J=8.5 Hz), 2.18 (2H, br s),1.95 (2H, br s), 1.54-1.51 (9H, m).

Elem. Anal.: C33H36ClN8NaO11S2(H2O) 6.7(NaHCO3) 0.1

Calcd.: C, 40.89; H, 5.13; N, 11.52; S, 6.59; Na, 2.60; Cl, 3.65(%).

Found: C, 40.70; H, 5.21; N, 11.60; S, 6.58; Na, 2.60; Cl, 3.84(%).

Example 104 and 105 Synthesis of Compound I-104 and I-105

Step (1): Compound 100a+Compound 96a→Compound 104a

Compound 96b (1.38 g, 11 mmol) was used to synthesize the targetcompound in the same way as in Step (1) of Example 102.

Yielded amount: 3 g (50%, E/Z=1:1.5)

Compound 104a

¹H-NMR (DMSO-D6) δ: 8.58 (1H, t, J=6.0 Hz), 8.33 (1H, t, J=6.0 Hz), 7.44(4H, d, J=7.7 Hz), 7.30 (4H, d, J=7.2 Hz), 7.25-7.14 (4H, m), 6.98 (4H,d, J=8.3 Hz), 6.86 (4H, d, J=8.3 Hz), 5.15 (4H, s), 4.88 (4H, s), 3.91(3H, s), 3.90 (3H, s), 3.77 (6H, s), 3.74 (6H, s), 2.78-2.73 (4H, m),2.47-2.42 (2H, m), 2.30 (2H, s), 2.16 (4H, s), 1.56-1.51 (4H, m),1.18-1.13 (4H, m).

Step (2): Compound X-24+Compound 104a→Compound I-104 and I-105

Compound X-24 (969 mg, 1.1 mmol) and compound 104a (650 mg, 1.1 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount of I-104: 140 mg (15%)

Compound 1-104

¹H-NMR (D₂O) δ: 7.02 (1H, s), 6.92 (2H, dd, J=20.5, 6.0 Hz), 5.83 (1H,d, J=4.8 Hz), 5.46 (1H, d, J=4.8 Hz), 4.90 (1H, d, J=14.3 Hz), 4.25 (1H,d, J=14.3 Hz), 4.03 (3H, s), 3.96-3.91 (1H, m), 3.72-3.53 (6H, m), 3.33(1H, d, J=8.5 Hz), 3.21 (1H, d, J=8.5 Hz), 2.18 (2H, s), 1.96 (2H, s),1.54-1.51 (9H, m).

Elem. Anal.: C34H38ClN8NaO11S2(H2O) 7.1(NaHCO3) 0.2

Calcd.: C, 41.00; H, 5.27; N, 11.18; S, 6.40; Na, 2.75; Cl, 3.54(%).

Found: C, 40.69; H, 5.23; N, 11.48; S, 6.36; Na, 2.99; Cl, 3.51(%).

Yielded amount of I-105: 180 mg (19%)

Compound I-105

¹H-NMR (D₂O) δ: 7.02 (1H, s), 6.95 (1H, d, J=8.4 Hz), 6.80 (1H, d, J=8.4Hz), 5.82 (1H, d, J=4.8 Hz), 5.48 (1H, d, J=4.8 Hz), 4.90 (1H, d, J=14.4Hz), 4.24 (1H, d, J=14.4 Hz), 4.03-3.95 (4H, m), 3.69-3.52 (6H, m), 3.35(1H, d, J=8.7 Hz), 3.22 (1H, d, J=8.7 Hz), 2.18 (2H, s), 1.95 (2H, s),1.55-1.51 (9H, m).

Elem. Anal.: C34H38ClN8NaO11S2(H2O) 6.8

Calcd.: C, 41.68; H, 5.31; N, 11.44; S, 6.54; Na, 2.35; Cl, 3.62(%).

Found: C, 41.46; H, 5.24; N, 11.61; S, 6.80; Na, 2.49; Cl, 3.60(%).

Example 106 Synthesis of Compound I-106

Step (1): Compound X-1+Compound 106a→Compound I-106

Compound X-1 (1.32 g, 1.32 mmol) and compound 106a (720 mg, 1.32 mmol)were used to synthesize the target compound in the same way as Example86.

Yielded amount: 510 mg (47%)

¹H-NMR (D₂O) δ: 8.26 (1H, s), 7.62 (1H, s), 7.30 (1H, s), 6.99 (1H, s),5.83 (1H, d, J=4.9 Hz), 5.48 (1H, d, J=4.9 Hz), 5.01 (1H, t, J=6.6 Hz),4.89 (1H, d, J=14.3 Hz), 4.54-4.47 (2H, m), 4.26 (1H, d, J=14.3 Hz),4.16-4.10 (1H, m), 3.59 (1H, s), 2.26-2.23 (4H, m), 1.58 (6H, t, J=6.6Hz), 1.53-1.49 (9H, m).

[M+H]=873.35

Example 107 Synthesis of Compound I-107

Step (1): Compound 107a→Compound 107b

Compound 107a (15.0 g, 99 mmol) was dissolved into dimethylacetamide(150 mL), and thereto were then added potassium carbonate (40.9 g, 296mmol), p-methoxybenzyl chloride (32.2 ml, 237 mmol) and sodium iodide(14.78 g, 99 mmol) in turn. The mixture was stirred at 50° C. for 1.5hours. The reaction mixture was poured into water. The precipitatedsolid was then collected by filtration, and washed with water anddiisopropyl ether. In this way, compound 107c was yielded (35.58 g 92%).

¹H-NMR (CDCl₃) δ: 7.60 (1H, s), 7.52 (1H, d, J=8.4 Hz), 7.36 (4H, m),6.93-6.89 (5H, m), 5.15 (2H, s), 5.11 (2H, s), 3.81 (6H, s), 2.51 (3H,s).

Step (2): Compound 107b→Compound 107c

Compound 107b (35.58 g, 91 mmol) was dissolved into pyridine (360 mL),and thereto was then added selenium dioxide (25.1 g, 227 mmol). Themixture was stirred at 80° C. for 1 day. The reaction mixture wasfiltered and evaporated. The residue was diluted with an aqueoushydrochloric acid solution and ethyl acetate, then separated and washedwith water and a saturated salt solution, and dried over magnesiumsulfate. Magnesium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The precipitated solid was thencollected by filtration, and, washed with diisopropyl ether to yieldcompound 107c (22.0 g, 57%).

¹H-NMR (DMSO-D₆) δ: 7.51-7.50 (2H, m), 7.39-7.35 (4H, m), 7.27 (1H, d,J=8.3 Hz), 6.95-6.93 (4H, m), 5.18 (2H, s), 5.10 (2H, s), 3.75 (3H, s),3.75 (3H, s).

Step (3): Compound 107c→Compound 107d

Compound 107c (4.00 g, 9.47 mmol) was dissolved into tetrahydrofuran (40mL), and thereto were then added 1-chloro-N, N,2-trimethyl-1-propenylamine (1.503 ml, 11.36 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 hr. Thereto were

was diluted with ethyl acetate and aqueous sodium hydroxide solution,then separated and washed with water and a saturated salt solution, anddried over magnesium sulfate. Magnesium sulfate was filtrated off, andthen the liquid was concentrated under reduced pressure. Theprecipitated solid was then collected.

¹H-NMR (DMSO-D₆) δ: 8.69 (1H, t, J=6.3 Hz), 7.56-7.55 (2H, m), 7.38-7.35(4H, m), 7.25 (1H, d, J=8.8 Hz), 6.95-6.92 (4H, m), 5.17 (2H, s), 5.07(2H, s), 3.75-3.75 (6H, m), 3.01 (2H, d, J=6.3 Hz), 2.76-2.73 (6H, m),1.34-1.31 (6H, m).

Step (4): Compound X-1+Compound 107d→Compound 107e→Compound I-107

Compound X-1 (932 mg, 1.0 mmol) was added to a solution of compound 107d(545 mg, 1.00 mmol) in dimethylformamide (2 mL) at 0° C., and theresultant solution was stirred at 0° C. for 3 hours. The reactionmixture was slowly added to a 5% salt solution (30 ml) (containing 1.5 gof sodium bisulfite) at 0° C. The precipitated solid was collected byfiltration, washed with water, and then suspended into water. Thesuspension was freeze-dried to yield compound 107e as an orange solid.Compound 107e was used in the next reaction without furtherpurification.

The total amount of compound 107e yielded was dissolved indichloromethane (10 mL), and the solution was cooled to −40° C. Theretowere then added anisole (1.3 mL, 12 mmol) and a 2 mol/L aluminumchloride solution (6.00 mL, 12 mmol) in nitromethane in turn. Theresultant was stirred at 0° C. for 30 minutes. The reaction mixture wasdissolved in water, a 2 mol/L aqueous hydrochloric acid solution, andacetonitrile. The resultant solution was then washed with diisopropylether. To the water phase was added HP20-SS resin, and then acetonitrilewas distilled off under reduced pressure. The resultant mixed liquid waspurified by ODS column chromatography. To the resultant target-compoundsolution was added HP20-SS resin, and then acetonitrile was distilledoff under reduced pressure. The resultant mixed liquid was purified byHP20-SS column chromatography. To the resultant target-compound solutionwas added a 0.2 N aqueous sodium hydroxide solution until the whole gavea pH of 6.0. Thereafter, a piece of dry ice was added thereto. Theresultant solution was concentrated under reduced pressure, and thenfreeze-dried to yield compound I-107 as a yellow powder.

Yielded amount: 592.4 mg, (64%).

¹H-NMR (D₂O) δ: 7.54-7.53 (2H, m), 7.00-6.99 (2H, m), 5.84 (1H, d, J=4.8Hz), 5.44 (1H, d, J=4.8 Hz), 4.65 (1H, d, J=14.4 Hz), 4.08-4.06 (2H, m),3.54-3.47 (6H, m), 3.37 (2H, s), 1.95-1.93 (6H, m), 1.56 (3H, d, J=7.1Hz), 1.53 (3H, s), 1.51 (3H, s).

Elem. Anal.: C34H38N7O11S2Na(H2O) 5.2

Calcd.: C, 45.30; H, 5.41; N, 10.88; S, 7.11; Na, 2.55(%).

Found: C, 45.00; H, 5.43; N, 11.26; S, 6.98; Na, 2.56(%).

Example 108 Synthesis of Compound I-108

Step (1): Compound 107c+Compound 108a→Compound 108b

Compound 107c (4.00 g, 9.47 mmol) and compound 108a (2.26 g, 11.36 mmol)were used to synthesize compound 108b in the same way as in Step 3 ofExample 107.

Yielded amount: 1.79 g, (36%)

¹H-NMR (DMSO-D₆) δ: 7.47-7.23 (7H, m), 6.95-6.93 (4H, m), 5.17 (2H, s),5.10 (2H, s), 4.51 (1H, s), 3.72-3.66 (7H, m), 2.98-2.73 (6H, m),2.00-1.98 (2H, m), 1.70-1.61 (3H, m).

Step (2): Compound X-1+Compound 108b→Compound 108c→Compound I-108

Compound X-1 (932 mg, 1.0 mmol) and compound 108b (531 mg, 1.0 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 661.3 mg, (67%)

¹H-NMR (D₂O) δ: 7.45-7.42 (2H, m), 7.03-6.99 (2H, m), 5.87-5.83 (1H, m),5.46-5.43 (1H, m), 4.95 (1H, br s), 4.85-4.81 (1H, m), 4.38-4.27 (1H,m), 4.16-4.07 (2H, m), 3.88-3.46 (7H, m), 2.47-2.22 (4H, m), 1.60-1.56(3H, m), 1.53-1.50 (6H, m).

Elem. Anal.: C33H36N7O11S2Na(H2O) 5.3

Calcd.: C, 44.57; H, 5.28; N, 11.03; S, 7.21; Na, 2.59(%).

Found: C, 44.53; H, 5.24; N, 11.33; S, 7.11; Na, 2.68(%).

Example 109 Synthesis of Compound I-109

Step (1): Compound 107c+Compound 109a→Compound 109b

Compound 107c (1.00 g, 2.37 mmol) and compound 109a (0.36 ml, 2.84 mmol)were used to synthesize compound 109b in the same way as in Step (3) ofExample 107.

Yielded amount: 459.4 mg, (37%)

¹H-NMR (DMSO-D₆) δ: 8.74 (1H, t, J=5.8 Hz), 7.65 (1H, dd, J=8.5, 1.8Hz), 7.58 (1H, d, J=1.8 Hz), 7.39-7.34 (4H, m), 7.21 (1H, d, J=8.5 Hz),6.96-6.91 (4H, m), 5.17 (2H, s), 5.08 (2H, s), 3.75 (3H, s), 3.75 (3H,s), 2.54 (2H, t, J=6.7 Hz), 2.49-2.46 (4H, m), 1.70-1.66 (4H, m).

Step (2): Compound X-1+Compound 109b→Compound 109c→Compound I-109

Compound X-1 (839 mg, 0.9 mmol) and compound 109b (467 mg, 0.9 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 415.0 mg, (52%)

¹H-NMR (D₂O) δ: 7.60 (1H, dd, J=8.5, 2.0 Hz), 7.55 (1H, d, J=2.0 Hz),7.01 (1H, s), 6.99 (1H, d, J=8.5 Hz), 5.80 (1H, d,

(2H, m), 3.73-3.67 (1H, m), 3.64-3.46 (5H, m), 2.28-2.20 (4H, m), 1.57(3H, d, J=7.0 Hz), 1.52 (3H, s), 1.50 (3H, s).

Elem. Anal.: C32H36N7O11S2Na(H2O) 4.5

Calcd.: C, 44.54; H, 5.26; N, 11.36; S, 7.43; Na, 2.66(%).

Found: C, 44.50; H, 5.18; N, 11.51; S, 7.10; Na, 2.68(%).

Example 110 Synthesis of Compound I-110

Step (1): Compound 110a→Compound 110b

Compound 110a (2.10 g, 5.00 mmol) was dissolved into ethanol (20 mL),and thereto was then added methyl hydrazine (0.28 ml, 5.25 mmol). Themixture was stirred at rt for 30 minutes, then reflux for 1 hour. Thereaction mixture was evaporated. The precipitated solid was thencollected by filtration, and washed with diisopropyl ether to yieldcompound 110b (2.28 g, 102%).

¹H-NMR (DMSO-D₆) δ: 7.68 (1H, s), 7.41-7.39 (5H, m), 6.96-6.94 (4H, m),5.22 (2H, s), 5.21 (2H, s), 3.75 (6H, s), 3.53 (3H, s).

Step (2): Compound 110b→Compound 110c

Compound 110b (1.20 g, 2.68 mmol) was dissolved into tetrahydrofuran (12mL), and thereto were then added diisopropyl azodicarboxylate (0.728 ml,3.75 mmol) and triphenylphosphine (983 mg, 3.75 mmol) at 0° C. Themixture was stirred at 0° C. for 10 minutes. Thereto was then added2-pyrrolidinoethanol (0.438 ml, 3.75 mmol) at 0° C. The mixture wasstirred at rt for 1 hour. Thereto was then added diisopropyl ether (24ml). The precipitated solid was then collected by filtration, and washedwith diisopropyl ether to yield compound 110c (0.93 g, 64%).

¹H-NMR (CDCl₃) δ: 7.82 (1H, s), 7.41-7.34 (5H, m), 6.91-6.89 (4H, m),5.22 (2H, s), 5.19 (2H, s), 4.42 (2H, t, J=5.9 Hz), 3.81 (3H, s), 3.81(3H, s), 3.70 (3H, s), 2.95 (2H, t, J=5.9 Hz), 2.67-2.62 (4H, m),1.85-1.78 (4H, m).

Step (3): Compound X-24+Compound 110c→Compound 110d→Compound I-110

Compound X-24 (886 mg, 1.0 mmol) and compound 110c (546 mg, 1.0 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 238.2 mg, (25%)

¹H-NMR (D₂O) δ: 7.45 (1H, s), 7.14 (1H, s), 7.01 (1H, s), 5.83 (1H, d,J=4.6 Hz), 5.47 (1H, d, J=4.6 Hz), 4.34 (1H, d, J=14.6 Hz), 4.08 (1H, q,J=6.9 Hz), 3.96-3.82 (3H, m), 3.74-3.47 (7H, m), 2.26 (4H, br s), 1.54(3H, d, J=6.9 Hz), 1.51 (3H, s), 1.49 (3H, s).

Elem. Anal.: C33H37N8O11S2Na(H2O) 5.8

Calcd.: C, 43.40; H, 5.36; N, 12.27; S, 7.02; Na, 2.52(%).

Found: C, 43.21; H, 5.29; N, 12.60; S, 6.97; Na, 2.65(%).

Example 111 Synthesis of Compound I-111

Step (1): Compound 111a+Compound 111b→Compound 111c

Compound 111a (10.0 g, 31.8 mmol) was dissolved into dimethylformamide(100 mL), and thereto was then added sodium hydride (3.05 g, 76.0 mmol)at 0° C. The mixture was stirred at 0° C. for 30 minutes. Thereto werethen added compound 111b (5.95 g, 35.0 mmol) and sodium iodide (9.54 g,63.6 mmol) in turn. The mixture was stirred at 60° C. for 2 hours. Thereaction mixture was diluted with ethyl acetate and water, thenseparated and washed with a saturated salt solution, and dried overmagnesium sulfate. Magnesium sulfate was filtrated off, and then theliquid was concentrated under reduced pressure. The compound-containingliquid was subjected to silica gel column chromatography to elute outthe desired compound with ethyl acetate (3% triethylamine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 111c (12.70 g, 97%).

¹H-NMR (DMSO-D₆) δ: 7.39-7.24 (10H, m), 5.19-4.95 (4H, m), 3.83-3.67(1H, m), 3.13 (1H, s), 3.07 (2H, s), 2.61-2.55 (1H, m), 2.45-2.36 (4H,m), 1.66-1.61 (4H, m).

Step (2): Compound 111c→Compound 111d

Compound 111c (12.70 g, 30.9 mmol) was dissolved into methanol (120 mL),and thereto was then added 10% Pd/C (2.54 g, 50% wet). The mixture wasstirred at rt under hydrogen atmosphere for 2 hours. The reactionmixture was filtered through celite, then concentrated under reducedpressure to yield compound 111d (4.90 g, 111%).

¹H-NMR (CDCl₃) δ: 3.94 (1H, t, J=6.8 Hz), 3.78 (1H, s), 2.96 (2H, t,J=6.8 Hz), 2.66-2.61 (3H, m), 2.58-2.52 (4H, m), 1.81-1.77 (4H, m).

Step (3): Compound 111d+Compound 110a→Compound 111e

Compound 111d (1.50 g, 10.47 mmol) was dissolved into ethanol (50 mL),and thereto was then added compound 110a (4.40 g, 10.47 mmol). Themixture was stirred at rt for 1 day, then reflux for 2 hour. Thereaction mixture was evaporated. The compound-containing liquid wassubjected to silica gel column chromatography to elute out the desiredcompound with ethyl acetate (3% triethylamine)/methanol. The

¹H-NMR (CDCl3) δ: 7.73 (1H, s), 7.73 (1H, s), 7.40-7.38 (4H, m),6.91-6.89 (4H, m), 5.21 (2H, s), 5.21 (2H, s), 4.30 (2H, t, J=7.3 Hz),3.81 (6H, s), 3.68 (3H, s), 2.73 (2H, t, J=7.3 Hz), 2.59-2.54 (4H, m),1.74-1.71 (4H, m).

Step (4): Compound X-24+Compound 111e→Compound 111f→Compound mmol) wereused to synthesize the target compound in the same way as in Step (4) ofExample 107.

Yielded amount: 444.5 mg, (46%)

¹H-NMR (D₂O) δ: 7.19 (1H, s), 7.14 (1H, s), 6.99 (1H, s), 5.81 (1H, d,J=4.8 Hz), 5.48 (1H, d, J=4.8 Hz), 5.12 (1H, d, J=14.1 Hz), 4.58 (2H, brs), 4.33 (1H, d, J=14.1 Hz), 4.11 (1H, q, J=6.9 Hz), 3.84-3.51 (9H, m),2.26 (4H, br s), 1.59 (3H d, J=6.9 Hz), 1.52 (3H, s), 1.50 (3H, s).

Elem. Anal.: C33H37N8O11S2Na(H2O) 6

Calcd.: C, 43.23; H, 5.39; N, 12.22; S, 6.99; Na, 2.51(%).

Found: C, 42.94; H, 5.30; N, 12.54; S, 6.85; Na, 2.64(%).

Example 112 Synthesis of Compound I-112

Step (1): Compound 110a→Compound 112a

Compound 110a (5.00 g, 11.89 mmol) was suspended into dimethylformamide(25 mL), and thereto were then added hexamethyldisilazane (24.93 ml, 119mmol) and methanol (0.48 ml, 11.89 mmol) in turn. The mixture wasstirred at rt for 1 day, then 50° C. for 2 hours, 80° C. for 2 hours.The reaction mixture was slowly added to a 1 mol/L aqueous hydrochloricacid solution (240 ml) at 0° C. The precipitated solid was collected byfiltration, washed with water and diisopropyl ether to yield compound112a (4.89 g, 98%).

¹H-NMR (CDCl₃) δ: 7.35 (4H, d, J=8.6 Hz), 7.33 (2H, s), 6.91 (4H, d,J=8.6 Hz), 5.18 (4H, s), 3.82 (6H, s).

Step (2): Compound 112a→Compound 112b

Compound 112a (1.00 g, 2.38 mmol) and paraformaldehyde (0.36 g, 11.92mmol) were suspended into dimethylformamide (10 mL), and thereto wasthen added pyrrolidine (0.99 ml, 11.92 mmol). The mixture was stirred atrt for 2 hours. Thereto was then added water (20 ml). The precipitatedsolid was then collected by filtration, and washed with water to yieldcompound 112b (1.16 g, 97%).

¹H-NMR (CDCl₃) δ: 7.37-7.34 (6H, m), 6.90 (4H, d, J=8.6 Hz), 5.18 (4H,s), 4.64 (2H, s), 3.82 (6H, s), 2.71-2.66 (4H, m), 1.74-1.70 (4H, m).

Step (3): Compound X-24+Compound 112b→Compound I-112

Compound X-24 (886 mg, 1.0 mmol) and compound 112b (503 mg, 1.0 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 111.0 mg, (9%)

¹H-NMR (D₂O) δ: 7.29 (2H, s), 7.01 (1H, s), 5.83 (1H, d, J=4.9 Hz), 5.48(1H, d, J=4.9 Hz), 4.27 (1H, d, J=14.4 Hz), 4.11 (1H, q, J=7.2 Hz), 3.72(1H, br s), 3.46-3.39 (3H, m), 3.28 (1H, t, J=7.2 Hz), 2.37-2.20 (4H,m), 2.00 (1H, t, J=7.2 Hz), 1.56 (3H, d, J=7.2 Hz), 1.52-1.49 (6H, m).

Elem. Anal.: C31H32N7O11S2Na(H2O) 5.2(NaHCO3) 0.2

Calcd.: C, 42.77; H, 4.90; N, 11.19; S, 7.32; Na, 3.15(%).

Found: C, 42.49; H, 4.85; N, 11.97; S, 7.87; Na, 3.14(%).

Example 113 Synthesis of Compound I-113

Step (1): Compound 113a→Compound 113b

Compound 113a (11.65 g, 51.0 mmol) was dissolved into dichloromethane(100 mL), and thereto were then added dropwise boron tribromide (25 g,100 mmol) and 1 mol/L dichloromethane solution of boron tribromide (20ml, 20 mmol) at 0° C. The mixture was stirred at rt for 1 hour. Thereaction mixture was diluted with ice water, then extracted with ethylacetate, and washed with a saturated salt solution, and dried overmagnesium sulfate. Magnesium sulfate was filtrated off, and then theliquid was concentrated under reduced pressure to yield compound 113b(10.60 g, 104%). Compound 113b was used in the next reaction withoutfurther purification.

¹H-NMR (DMSO-D₆) δ: 10.54 (2H, br s), 7.09 (1H, s), 5.22 (2H, s).

Step (2): Compound 113b→Compound 113c

The total amount of compound 113b obtained in Step (1) was dissolvedinto dimethylacetamide (110 mL), and thereto were then added potassiumcarbonate (21.9 g, 159 mmol), p-methoxybenzyl chloride (17.3 ml, 127mmol) and sodium iodide (7.92 g, 52.8 mmol) in turn. The mixture wasstirred at 50° C. for 1 hour. The reaction mixture was poured intowater. The precipitated solid was then collected by filtration, andwashed with water and diisopropyl ether to yield compound 113c (20.71 g,89%).

¹H-NMR (CDCl₃) δ: 7.39-7.36 (3H, m), 7.30 (2H, d, J=8.6 Hz), 6.94 (2H,d, J=8.6 Hz), 6.83 (2H, d, J=8.6 Hz), 5.18 (2H, s), 5.11 (2H, s), 5.09(2H, s), 3.84 (3H, s), 3.80 (3H, s).

Step (3): Compound 113c→Compound 113d

A 2 mol/L aqueous sodium hydroxide solution (15 ml, 30 mmol) was addedto a solution of compound 113c (4.41 g, 10 mmol) in tetrahydrofuran (5mL) and methanol (5 mL). The resultant solution was stirred at 70° C.for 1 hour. To the reaction mixture was added water and 2 mol/L aqueoushydrochloric acid solutions (18 mL) at 0° C. The precipitated solid wasthen collected by filtration, and washed with water to yield compound113d (5.33 g, 116%).

¹H-NMR (CDCl₃) δ: 7.61 (1H, s), 7.37-7.32 (4H, m), 6.92 (2H, d, J=7.9Hz), 6.83 (2H, d, J=7.4 Hz), 5.09 (2H, s), 5.04 (2H, s), 4.98 (2H, s),3.83 (3H, s), 3.80 (3H, s).

Step (4): Compound 113d→Compound 113e

The total amount of compound 113d yielded (5.33 g, 10 mmol) wassuspended into acetone (50 mL), and thereto was then added Jone'sreagent (2.67 mol/L, 7.5 mL, 20 mmol) at 0° C. The mixture was stirredat rt for 30 minutes. The reaction mixture was diluted with water, thenadded sodium bisulfite at 0° C. The mixture was evaporated to removeacetone, then the precipitated solid was collected by filtration, washedwith water and diisopropyl ether to yield compound 113e (3.75 g, 82%).

¹H-NMR (CDCl₃) δ: 7.39-7.37 (3H, m), 7.31 (2H, d, J=8.3 Hz), 6.94 (2H,d, J=8.4 Hz), 6.83 (2H, d, J=8.3 Hz), 5.18 (1H, s), 5.11-5.07 (4H, m),3.84 (3H, s), 3.80 (3H, s).

Step (5): Compound 113e+Compound 113f→Compound 113g

Compound 113e (777 mg, 3.40 mmol) was dissolved into dimethylacetamide(30 mL), and thereto was then added sodium acetate (1.40 g, 17.0 mmol).The mixture was stirred at rt for 30 minutes. Thereto was then addedcompound 113f (3.11 g, 6.81 mmol). The mixture was stirred at rt for 1hour, then 70° C. for 1 hour. The reaction mixture was diluted withethyl acetate and aqueous sodium hydroxide solution, then separated andwashed with water and a saturated salt solution, and dried over sodiumsulfate. Sodium sulfate was filtrated off, and then the liquid wasconcentrated under reduced pressure. The compound-containing liquid wassubjected to silica gel column chromatography to elute out the desiredcompound with ethyl acetate (10% triethylamine)/methanol (10%triethylamine). The desired-compound-containing fraction wasconcentrated under reduced pressure to yield compound 113g (553 mg,12%).

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, s), 7.84 (1H, s), 7.49 (2H, d, J=8.3 Hz),7.29 (2H, d, J=8.3 Hz), 7.01 (2H, d, J=8.3 Hz), 6.86 (2H, d, J=8.3 Hz),5.33 (2H, s), 5.09 (2H, s), 3.96 (2H, s), 3.79 (3H, s), 3.74 (3H, s),2.71 (6H, br s), 1.39 (6H, br s).

Step (6): Compound X-24+Compound 113g→Compound 113h→Compound I-113

Compound X-24 (886 mg, 1.0 mmol) and compound 113g (553 mg, 960 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 547.4 mg, (58%)

¹H-NMR (D₂O) δ: 8.38 (1H, s), 7.37 (1H, s), 6.99 (1H, s), 5.83 (1H, d,J=4.9 Hz), 5.43 (1H, d, J=4.9 Hz), 4.61 (1H, d, J=14.4 Hz), 4.17 (2H,s), 4.09-4.02 (2H, m), 3.55-3.38 (6H, m), 1.99 (6H, s), 1.54 (3H, d,J=7.2 Hz), 1.51 (3H, s), 1.50 (3H, s).

Elem. Anal.: C34H36ClN8O10S2Na(H2O) 5(NaHCO3) 0.4

Calcd.: C, 42.91; H, 4.86; N, 11.64; S, 6.66; Na, 3.34(%).

Found: C, 42.74; H, 4.97; N, 12.01; S, 6.81; Na, 3.33(%).

Example 114 and 115 Synthesis of Compound I-114 and I-115

Step (1): Compound 114a+Compound 113f→Compound 114b

Compound 113f (311 mg, 1.36 mmol) and sodium acetate (559 mg, 6.82 mmol)were suspended into tetrahydrofuran (6 mL), and thereto was then addedsuspension of compound 114a (0.62 g, 1.36 mmol) in tetrahydrofuran (6mL) at −20° C. The mixture was stirred at −20° C. for 1 hour. Theretowas then added acetic acid (0.39 ml, 6.82 mmol). The mixture was stirredat reflux for 1 day. The reaction mixture was diluted with ethyl acetateand aqueous sodium hydroxide solution, then separated and washed withwater and a saturated salt solution, and dried over sodium sulfate.Sodium sulfate was filtrated off, and then the liquid was concentratedunder reduced pressure. The precipitated solid was then collected byfiltration, and washed with diisopropyl ether to yield a mixture ofcompound 114b and 114c (206 mg, 26%). The mixture was used in the nextreaction without further purification.

MS (m+1)=592

Step (2): Compound X-24+Compound 114b and 114c→Compound I-114 and I-115

Compound X-24 (354 mg, 0.4 mmol) and compound 114b and 114c (206 mg,0.35 mmol) were used to synthesize the target compound in the same wayas in Step (4) of Example 107.

Yielded amount: Compound I-114 (165.6 mg, 45%), compound I-115 (16.6 mg,5.5%)

Compound I-114

¹H-NMR (D₂O) δ: 7.10 (1H, s), 7.01 (1H, s), 5.85 (1H, d, J=4.6 Hz), 5.45(1H, d, J=4.6 Hz), 4.63 (1H, d, J=13.9 Hz), 4.12-4.05 (2H, m), 3.59-3.41(6H, m), 2.98 (2H, s), 1.97 (6H, t, J=7.2 Hz), 1.57 (3H, d, J=6.9 Hz),1.52 (3H, s), 1.51 (3H, s).

Elem. Anal.: C34H36ClN8O11S2Na(H2O) 6.2(NaHCO3) 0.5

Calcd.: C, 41.07; H, 4.89; Cl, 3.51; N, 11.11; S, 6.36; Na, 3.42(%).

Found: C, 40.68; H, 4.96; Cl, 3.53; N, 11.52; S, 6.41; Na, 3.32(%).

Compound I-115

¹H-NMR (D₂O) δ: 7.33 (1H, s), 6.92 (1H, s), 5.76 (1H, d, J=4.4 Hz), 5.36(1H, d, J=4.4 Hz), 4.55 (1H, d, J=14.3 Hz), 3.99-3.91 (4H, m), 3.50-3.32(6H, m), 1.96-1.92 (6H, m), 1.48-1.43 (9H, m).

MS (m+1)=833

Example 116 Synthesis of Compound I-116

Step (1): Compound 110a+Compound 116a→Compound 116b

Compound 110a (1.26 g, 3.0 mmol) and compound 116a (379 mg, 3.0 mmol)were used to synthesize compound 116b in the same way as ReferenceExample 5.

Yielded amount: 1.35 g, (85%)

¹H-NMR (DMSO-D₆) δ: 7.49 (2H, s), 7.38 (4H, d, J=8.7 Hz), 6.95 (4H, d,J=8.7 Hz), 5.24 (4H, s), 3.82 (2H, s), 3.75 (6H, s), 2.74-2.68 (2H, m),2.44-2.38 (2H, m), 2.11 (2H, s), 1.50-1.44 (2H, m), 1.14-1.08 (2H, m).

Step (2): Compound X-24+Compound 116b→Compound 116c→Compound I-116

Compound X-24 (886 mg, 1.0 mmol) and compound 116b (529 mg, 1.0 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 568.0 mg, (62%)

¹H-NMR (D₂O) δ: 7.21 (2H, s), 7.00 (1H, s), 5.79 (1H, d, J=4.9 Hz), 5.40(1H, d, J=4.9 Hz), 4.23 (1H, d, J=14.6 Hz), 4.06 (1H, q, J=7.2 Hz), 3.91(2H, s), 3.70-3.47 (4H, m), 3.43 (1H, d, J=8.5 Hz), 3.33 (1H, d, J=8.5Hz), 2.23-2.13 (2H, m), 2.00-1.92 (2H, m), 1.55 (3H, d, J=7.2 Hz), 1.52(3H, s), 1.50 (3H, s).

Elem. Anal.: C33H34N7O11S2Na(H2O) 6.3

Calcd.: C, 43.78; H, 5.19; N, 10.83; S, 7.08; Na, 2.54(%).

Found: C, 43.76; H, 5.19; N, 10.87; S, 7.02; Na, 2.59(%).

Example 117 Synthesis of Compound I-117

Step (1): Compound 117a→Compound 117b

Compound 117a (1.24 g, 3.0 mmol) and 1-hydroxybenzotriazole (446 mg, 3.3mmol) were dissolved into dichloromethane (15 mL), and thereto was thenadded 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (690mg, 3.6 mmol) at 0° C. The mixture was stirred at rt for 1 hour. Thereaction mixture was diluted with dichloromethane and an aqueoushydrochloric acid solution, then separated and washed with water, asaturated sodium bicarbonate solution, and a saturated salt solution,and dried over magnesium sulfate. Magnesium sulfate was filtrated off,and then the liquid was concentrated under reduced pressure to yieldcompound 117b (1.72 g, 108%).

Compound 117b was used as it was, without being purified, in the nextreaction.

¹H-NMR (CDCl₃) δ: 8.11 (1H, d, J=8.7 Hz), 7.68-7.62 (2H, m), 7.58-7.54(1H, m), 7.47-7.44 (2H, m), 7.36 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5Hz), 6.93 (2H, d, J=8.5 Hz), 6.85 (2H, d, J=8.5 Hz), 5.23 (2H, s), 5.12(2H, s), 3.83 (3H, s), 3.81 (3H, s).

Step (2): Compound 117b+Compound 116a→Compound 117c

Compound 117b (1.59 g, 3.0 mmol) was dissolved into tetrahydrofuran (10mL), and thereto was then added compound 116a (379 mg, 3.0 mmol) intetrahydrofuran (10 mL) at 0° C. The mixture was stirred at rt for 1hour. The reaction mixture was diluted with ethyl acetate and aqueoussodium hydroxide solution, then separated and washed with water and asaturated salt solution, and dried over sodium sulfate. Sodium sulfatewas filtrated off, and then the liquid was concentrated under reducedpressure. The compound-containing liquid was subjected to silica gelcolumn chromatography to elute out the desired compound with ethylacetate (10% triethylamine)/methanol (10% triethylamine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 117b (1.54 g, 99%).

¹H-NMR (DMSO-D₆) δ: 8.53 (1H, t, J=5.9 Hz), 7.48 (1H, s), 7.43 (2H, d,J=8.0 Hz), 7.33 (1H, d, J=11.0 Hz), 7.25 (2H, d, J=8.0 Hz), 6.98 (2H, d,J=8.0 Hz), 6.85 (2H, d, J=8.0 Hz), 5.14 (2H, s), 5.01 (2H, s), 3.78 (3H,s), 3.73 (3H, s), 3.58 (2H, d, J=5.9 Hz), 2.83-2.76 (2H, m), 2.20 (2H,s), 1.58-1.52 (2H, m), 1.21-1.15 (2H, m).

Step (3): Compound X-24+Compound 117c→Compound 117d→Compound I-117

Compound X-24 (886 mg, 1.0 mmol) and compound 117c (521 mg, 1.0 mmol)were used to synthesize the target compound in the same way as in Step(4). of Example 107.

Yielded amount: 202.3 mg, (22%)

¹H-NMR (D₂O) δ: 7.17 (1H, d, J=11.0 Hz), 7.13 (1H, s), 7.00 (1H, s),5.79 (1H, d, J=4.0 Hz), 5.41 (1H, d, J=4.0 Hz), 4.89 (1H, d, J=14.7 Hz),4.25 (1H, d, J=14.2 Hz), 4.05 (1H, q, J=7.2 Hz), 3.69-3.56 (6H, m), 3.40(1H, d, J=8.4 Hz), 3.31 (1H, d, J=8.4 Hz), 2.25-2.17 (2H, m), 1.99-1.93(2H, m), 1.55 (3H, d, J=7.2 Hz), 1.52 (3H, s), 1.50 (3H, s).

Elem. Anal.: C32H35FN7O10S2Na(H2O) 6.7(NaHCO3) 0.1

Calcd.: C, 42.23; H, 5.36; F, 2.08; N, 10.74; S, 7.02; Na, 2.77(%).

Found: C, 42.17; H, 5.21; F, 2.02; N, 10.91; S, 7.06; Na, 2.77(%).

Example 118 Synthesis of Compound I-118

Step (1): Compound 118a Compound 118b+Compound 118c→Compound 118d

Compound 118a was used to synthesize compound 118b in the same way as inStep (1). Of Example 117.

Compound 118a (1.67 g, 3.1 mmol) and compound 118b (472 mg, 3.1 mmol)were used to synthesize compound 118c in the same way as in Step (2) ofExample 117.

Yielded amount: 1.36 g, (79%)

¹H-NMR (DMSO-D₆) δ: 8.23 (1H, t, J=6.2 Hz), 7.43 (2H, d, J=8.5 Hz), 7.33(2H, d, J=8.5 Hz), 7.18 (1H, d, J=8.5 Hz), 7.12 (1H, d, J=8.5 Hz), 6.97(2H, d, J=8.5 Hz), 6.88 (2H, d, J=8.5 Hz), 5.15 (2H, s), 4.88 (2H, s),3.77 (3H, s), 3.75 (3H, s), 2.97-2.84 (6H, m), 2.60 (2H, s), 2.03-1.90(2H, m), 1.68-1.53 (4H, m), 1.46-1.39 (2H, m).

Step (2): Compound X-24+Compound 118d→Compound 118e→Compound I-118

Compound X-24 (886 mg, 1.0 mmol) and compound 118d (565 mg, 1.0 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 579.6 mg, (61%)

¹H-NMR (D₂O) δ: 6.96 (1H, d, J=8.3 Hz), 6.94 (1H, s), 6.90 (1H, d, J=8.3Hz), 5.80 (1H, d, J=4.8 Hz), 5.43 (1H, d, J=4.8 Hz), 4.13 (1H, d, J=14.1Hz), 3.98 (1H, q, J=7.2 Hz), 3.76-3.71 (1H, m), 3.50-3.13 (7H, m),2.56-2.44 (2H, m), 2.02-1.95 (2H, m), 1.88-1.69 (4H, m), 1.55 (3H, d,J=7.2 Hz), 1.50 (3H, s), 1.48 (3H, s).

Elem. Anal.: C34H39ClN7O10S2Na(H2O) 6.4

Calcd.: C, 43.28; H, 5.53; Cl, 3.76; N, 10.39; S, 6.80; Na, 2.44(%).

Found: C, 43.17; H, 5.41; Cl, 3.69; N, 10.57; S, 6.85; Na, 2.47(%).

Example 119 Synthesis of Compound I-119

Step (1): Compound 119a→Compound 119b

Compound 119a (2.53 g, 10.0 mmol) was dissolved into methanol (12.5 mL),and thereto was then added 4 mol/L dioxane solution of hydrochloric acid(12.5 ml, 50 mmol) at 0° C. The mixture was stirred at rt for 4 hours,then the reaction mixture was evaporated. The precipitated solid wasthen collected by filtration, and washed with ethyl acetate/methanol(1/1) and ethyl acetate. The precipitated solid was suspended intomethanol (25 mL), and thereto was then added sodium hydroxide (1.20 g,30 mmol). The mixture was stirred at rt for 30 minutes, then a piece ofdry ice was added thereto. The mixture was filtered, then the filtratewas concentrated under reduced pressure to yield compound 119b (2.67 g,174%). The mixture was used in the next reaction without furtherpurification.

MS (m+1)=154

Step (2): Compound 119b+Compound 118b→Compound 119c

Compound 118a (1.09 g, 2.0 mmol) and compound 119b (538 mg, 2.0 mmol)were used to synthesize compound 119c in the same way as in Step (2) ofExample 117.

Yielded amount: 0.47 g, (42%)

MS (m+1)=564

Step (3): Compound X-24+Compound 119c→Compound 119d→Compound I-119

Compound X-24 (722 mg, 0.82 mmol) and compound 119c (460 mg, 0.82 mmol)were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 13 mg, (1.7%)

¹H-NMR (D₂O) δ: 7.58 (1H, s), 7.01 (1H, s), 6.75 (3H, s), 5.85 (1H, s),5.46 (1H, d, J=5.3 Hz), 4.14-4.10 (4H, m), 3.62-3.55 (8H, m), 2.18 (6H,br s), 1.60-1.51 (9H, m).

MS (m+1)=783

Example 120 Synthesis of Compound I-130

Step (1): Compound X-24+Compound 120a→Compound 120b→Compound I-120

A solution of Compound 120a (658 mg, 1.0 mmol) in dimethylformamide (2.0mL) was cooled with ice. The reaction vessel was then degassed underreduced pressure, and thereto was added Compound X-24 (886 mg, 1.0mmol). After stirring at 0° C. for 6 hours, the reaction mixture wasslowly added to 5% aqueous sodium chloride and sodium hydrogen sulfitesolution it was cooled with ice. The precipitated solid was collected byfiltration, washed with water, and suspended into water. The suspensionwas freeze-dried to yield Compound 120b as a brown solid. Compound 120byielded was used as it was, without being purified, in the nextreaction.

The total amount of compound 120b yielded was dissolved indichloromethane (10 mL), and the solution was cooled to −40° C. Theretowas then added anisole (1.09 mL, 10 mmol) and a 2 mol/L aluminumchloride solution (5.0 mL, 10 mmol) in nitromethane in turn. The liquidwas stirred at 0° C. for 30 minutes. To the reaction liquid was addeddiisopropyl ether and a small amount of water, and the resultant wasstirred to generate a precipitate. The supernatant was removed bydecantation. To the insoluble matter adhering to the vessel were added adiluted aqueous hydrochloric acid solution, and acetonitrile. Theresultant was stirred to dissolve the matter completely. Thereto wasthen added diisopropyl ether, and the water phase was separated to becollected. The organic phase was again subjected to extraction withwater, and then all of the resultant water phases were combined witheach other. Thereto was added HP20-SS resin. Acetonitrile was thendistilled off therefrom under reduced pressure. The resultant mixedliquid was purified by ODS column chromatography. Thedesired-compound-containing fraction was added 0.2 mol/L sodiumhydroxide aqueous solution until it gave a pH of 6.0, and thereto wasadded a piece of dry ice. The resultant solution was concentrated underreduced pressure, and then freeze-dried to yield compound I-120 as ayellow powder.

Yielded amount: 534 mg (58%)

¹H-NMR (D₂O) δ: 1.06 (2H, s), 1.29 (2H, d, J=6.65 Hz), 1.51 (3H, s),1.53 (3H, s), 1.59 (3H, d, J=6.78 Hz), 2.06 (2H, t, J=13.55 Hz),2.44-2.83 (5H, m), 3.13 (3H, s), 3.44 (1H, s), 4.01-4.22 (5H, m), 5.47(1H, d, J=4.77 Hz), 5.83 (1H, d, J=4.77 Hz), 7.00 (1H, s), 7.23 (1H, s),8.34 (1H, s).

Elem. Anal.: C₃₉H42 ClN₈O₁₁S₂Na.7.0H₂O.0.1 NaHCO₃

Calcd.: C, 44.48; H, 5.36; Cl, 3.36; N, 10.61; S, 6.07; Na, 2.40(%).

Found: C, 44.18; H, 5.34; Cl, 3.27; N, 10.91; S, 6.27; Na, 2.43(%).

MS (m+1)=899.38

Example 121 Synthesis of Compound I-121

Step (1): Compound X-24+Compound 121a→Compound 121b→Compound I-121

From Compound X-24 (886 mg, 1.0 mmol) and Compound 121a (646 mg, 1.0mmol), Compound I-121 was obtained as a yellow powder using the samemethod as Example 120.

Yielded amount: 127 mg, (14%)

¹H-NMR (D₂O) δ: 1.41 (3H, t, J=6.90 Hz), 1.51 (3H, s), 1.53 (3H, s),1.59 (3H, d, J=6.90 Hz), 2.07-2.14 (2H, m), 2.45-2.87 (6H, m), 3.13 (3H,s), 4.00-4.29 (8H, m), 5.47 (1H, d, J=4.77 Hz), 5.83 (1H, d, J=4.77 Hz),6.79 (1H, s), 7.01 (1H, s), 8.44 (1H, s).

MS (m+1)=887.32

Example 122 Synthesis of Compound I-122

Step (1): Compound 122a→Compound 122b→Compound 122c

A solution of Compound 122a (22.84 g, 168 mmol) in toluene (114 mL) wascooled to −78° C., and thereto was added dropwise 1 mol/L DIBAL solution(335 mL, 335 mmol) in toluene for 50 minutes. After stirring at −78° C.for 50 minutes, the reaction mixture was warmed to 0° C., and theretowas added dropwise water (13.4 mL), 15% sodium hydroxide aqueoussolution (13.4 mL), and water (33.5 mL) at 0° C. After stirring at roomtemperature for 10 minutes thereto was added methanol (114 mL), andtert-butyl hydrazinecarboxylate (26.6 g, 201 mmol). After stirring atroom temperature for overnight, the insoluble substance was removed byfiltration, and then concentrated. The residue was dissolved ethylacetate and added saturated citric acid aqueous solution until it gave apH of 4.0. The water phase was separated and added 8 mol/L sodiumhydroxide aqueous solution until it gave a pH of 12.0, followed byextraction with chloroform twice time. The combined organic layer wasdried with anhydrous sodium sulfate. The inorganic substance was removedby filtration, and then concentrated under reduced pressure. Thereto wasadded diisopropyl ether to precipitate a solid. The solid was collectedby filtration, so as to yield compound 122c as a white solid.

Yielded amount: 28.7 g (68%)

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 1.60 (6H, t, J=7.72 Hz), 2.91 (6H, t,J=7.72 Hz), 6.92 (1H, s), 7.56 (1H, s).

Step (2): Compound 122c→Compound 122d→Compound 122e

A solution of Compound 122c (28.7 g, 113 mmol) in methanol (144 mL) wascooled with ice, and thereto was added sodium cyanoborohydride (14.24 g,227 mmol), and then added 2 mol/L hydrochloric acid aqueous solutionuntil it gave a pH of 4.0. After stirring at room temperature for 1.5hours, and thereto was added 8 mol/L sodium hydroxide aqueous solutionuntil it gave a pH of 12.0 at 0° C., and then concentrated, followed byextraction with ethyl acetate twice time. The combined organic layer waswashed with saturated brine, and then was dried with anhydrous sodiumsulfate. The inorganic substance was removed by filtration, and thenconcentrated and subsequently drying under reduced pressure to yieldCompound 122d as a orange oil. Compound 122d yielded was used as it was,without being purified, in the next reaction.

The total amount of compound 122d yielded was dissolved in methanol (144mL), and the solution was cooled with ice. Thereto was added slowly 4mol/L hydrochloric acid solution (141 mL, 565 mmol) in 1,4-dioxane.After stirring at room temperature for overnight, and the reactionmixture was concentrated under reduced pressure. Thereto was added 50%methanol/ethyl acetate solution to precipitate a solid. The solid wascollected by filtration, so as to yield compound 122e as a white solid.

Yielded amount: 24.6 g (95%)

¹H-NMR (D₂O) δ: 1.90 (6H, t, J=7.97 Hz), 2.99 (2H, s), 3.39 (6H, t,J=7.97 Hz).

Step (3): Compound 122e+Compound 110a→Compound 122f

A suspension of Compound 122e (17.6 g, 77 mmol) in 1,4-dioxane (144 mL)was added sodium acetate (31.6 g, 385 mmol) and Compound 110a (38.8 g,92 mmol). After stirring at room temperature for 1 hour, thereto wasadded acetic acid (22.02 ml, 385 mmol). After stirring at roomtemperature for overnight, thereto was stirred at 70° C. for 1.5 hours.Then thereto was added 2 mol/L sodium hydroxide aqueous solution untilit gave a pH of 12.0 at 0° C., followed by extraction with ethyl acetatetwice time. The combined organic layer was washed with saturated brine,and then was dried with anhydrous sodium sulfate. The inorganicsubstance was removed by filtration, and then concentrated under reducedpressure. Thereto was added 5% triethylamine and methanol solution inethyl acetate to precipitate a solid. The solid was collected byfiltration, so as to yield compound 122f as a white solid.

Yielded amount: 30.96 g (72%)

¹H-NMR (DMSO-D₆) δ: 1.40 (6H, t, J=7.47 Hz), 2.64 (6H, t, J=7.47 Hz),3.59 (2H, s), 3.75 (6H, s), 5.11 (2H, s), 5.12 (2H, s), 6.94 (4H, d,J=8.28 Hz), 7.38 (4H, d, J=8.28 Hz), 7.52 (2H, s).

Step (4): Compound X-24+Compound 122f→Compound 122g→Compound I-122

From Compound X-24 (10.0 g, 11.3 mmol) and Compound 122f (6.31 g, 11.3mmol), Compound I-122 was obtained as a white powder using the samemethod as Example 120.

Yielded amount: 3.68 g, (40%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.51 (3H, s), 1.53 (3H, d, J=7.53 Hz),2.00 (6H, t, J=7.22 Hz), 3.38-3.55 (6H, m), 3.97-4.06 (4H, m), 4.61 (1H,d, J=14.43 Hz), 5.42 (1H, d, J=4.77 Hz), 5.83 (1H, d, J=4.77 Hz), 6.97(1H, s), 7.24 (1H, s), 7.39 (1H, s).

Elem. Anal.: C₃₃H₃₇N₈O₁₁S₂Na_(1.2).5.9H₂O

Calcd.: C, 43.83; H, 5.28; N, 12.03; S, 6.88; Na, 2.96(%).

Found: C, 43.74; H, 5.35; N, 12.27; S, 7.03; Na, 2.86(%).

MS (m+1)=799.23

Example 123 Synthesis of Compound (I-123)

Step (1): Compound 122a→Compound 122b→Compound 123a

From Compound 122a (10.0 g, 73.4 mmol) and benzyl hydrazinecarboxylate(21.96 g, 132 mmol), Compound 123a was obtained as a white powder usingthe same method as in Step (1) of Example 122.

Yielded amount: 14.02 g, (66%)

¹H-NMR (DMSO-D₆) δ: 1.44 (6H, t, J=7.58 Hz), 2.74 (6H, t, J=7.58 Hz),5.04 (2H, s), 7.09 (1H, s), 7.31-7.40 (6H, m).

Step (2): Compound 123a→Compound 123b

A solution of Compound 123a (11.49 g, 40 mmol) in methanol (180 mL) wasadded 5% palladium on carbon (3.6 g, 1.7 mmol). After stirring underhydrogen (1 atm) at room temperature for 2 hours, the insolublesubstance was removed by filtration. Thereto was concentrated andsubsequently drying under reduced pressure to yield Compound 123b as awhite solid.

Yielded amount: 5.97 g, (97%)

¹H-NMR (DMSO-D₆) δ: 1.40 (6H, t, J=7.65 Hz), 2.73 (6H, t, J=7.65 Hz),5.88 (2H, s), 6.76 (1H, s).

Step (3): Compound 123b+Compound 110a→Compound 123c

A suspension of Compound 123b (6.97 g, 45.5 mmol) in dimethylformamide(70 mL) was added Compound 110f (20.08 g, 47.8 mmol) at 0° C. Afterstirring at room temperature for 2 hours, thereto was addedO-Benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (20.70g, 54.6 mmol) at 0° C. After stirring at room temperature for 4 hours,thereto was added acetic acid (26.0 ml, 455 mmol) and sodiumcyanoborohydride (4.29 g, 68.2 mmol) at 0° C. After stirring at roomtemperature for overnight, thereto was added 2 mol/L sodium hydroxideaqueous solution, followed by extraction with ethyl acetate twice time.The combined organic layer was washed with water and saturated brine,and then was dried with anhydrous sodium sulfate. The inorganicsubstance was removed by filtration, and then concentrated under reducedpressure. Thereto was added diisopropyl ether to precipitate a solid.The solid was collected by filtration, so as to yield compound 123c as ayellow solid.

Yielded amount: 14.19 g, (56%)

¹H-NMR (DMSO-D₆) δ: 1.37 (6H, t, J=7.59 Hz), 2.65 (2H, d, J=6.02 Hz),2.73 (6H, t, J=7.59 Hz), 3.75 (6H, s), 5.23 (4H, s), 6.95 (4H, d, J=8.66Hz), 7.37 (4H, d, J=8.66 Hz), 7.46 (2H, s).

Step (4): Compound X-24+Compound 123c→Compound I-123

From Compound X-24 (11.52 g, 13 mmol) and Compound 123c (7.25 g, 13mmol), Compound I-123 was obtained as a white powder using the samemethod as Example 120.

Yielded amount: 3.25 g, (30%)

¹H-NMR (D₂O) δ: 1.51 (3H, s), 1.52 (3H, s), 1.57 (3H, d, J=7.15 Hz),1.97 (6H, t, J=7.65 Hz), 2.98 (2H, s), 3.41-3.58 (6H, m), 4.05-4.12 (2H,m), 4.63 (1H, d, J=14.81 Hz), 5.45 (1H, d, J=4.89 Hz), 5.85 (1H, d,J=4.89 Hz), 7.00 (1H, s), 7.19 (2H, s).

MS (m+1)=799.23

Example 124 Synthesis of Compound I-124

Step (1): Compound 124a→Compound 124b

A solution of Compound 124a (30.5 g, 72 mmol) in tetrahydrofuran (305mL) was added manganese dioxide (62.5 g, 719 mmol). After stirring atroom temperature for overnight, the insoluble substance was removed byfiltration. And thereto was added 1 mol/L hydrochloric acid aqueoussolution, followed by extraction with ethyl acetate twice time. Thecombined organic layer was washed with saturated brine, and then wasdried with anhydrous magnesium sulfate. The inorganic substance wasremoved by filtration, and then concentrated under reduced pressure.Thereto was added diisopropyl ether to precipitate a solid. The solidwas collected by filtration, so as to yield compound 124b as a brownsolid.

Yielded amount: 22.76 g (75%)

¹H-NMR (DMSO-D₆) δ: 3.75 (3H, s), 3.76 (3H, s), 5.16 (2H, s), 5.17 (2H,s), 6.92-6.96 (4H, m), 7.35-7.40 (6H, m).

Step (2): Compound 124b+Compound 122e→Compound 5124cc

A solution of Compound 124b (30 g, 71 mmol) in dimethylformamide (300mL) was added Compound 122e (19.44 g, 85 mmol) and sodium acetate (29.1g, 355 mmol). After stirring at room temperature for 1 hour, thereto wasadded acetic acid (20.3 ml, 355 mmol). After stirring at roomtemperature for over night, thereto was added ice water and 2 mol/Lsodium hydroxide aqueous solution until it gave a pH of 10.0 at 0° C.The precipitated solid was then collected by filtration and dissolvedtetrahydrofuran. The resultant solution was dried with anhydrous sodiumsulfate. The inorganic substance was removed by filtration, and thenconcentrated under reduced pressure. Thereto was added ethyl acetate toprecipitate a solid. The solid was collected by filtration, so as toyield compound 124c as a white solid.

Yielded amount: 32.66 g (85%)

¹H-NMR (DMSO-D₆) δ: 1.42 (6H, t, J=7.59 Hz), 2.75 (6H, t, J=7.59 Hz),3.75 (6H, s), 3.94 (2H, s), 5.20 (2H, s), 5.22 (2H, s), 6.94-6.97 (4H,m), 7.39 (2H, d, J=8.53 Hz), 7.42 (2H, d, J=8.53 Hz), 7.54 (1H, s), 7.71(1H, s), 8.21 (1H, s).

Step (3): Compound X-24+Compound 124c→Compound I-124

From Compound X-24 (886 mg, 1.0 mmol) and Compound 124c (541 mg, 1.0mmol), Compound I-124 was obtained as a yellow powder using the samemethod as Example 120.

Yielded amount: 440 mg, (55%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.54 (3H, d, J=7.40 Hz),1.98 (6H, s), 3.47 (6H, d, J=34.88 Hz), 4.02-4.13 (4H, m), 4.62 (1H, d,J=14.68 Hz), 5.42 (1H, d, J=4.77 Hz), 5.83 (1H, d, J=4.77 Hz), 6.97 (1H,s), 7.08 (1H, s), 7.41 (1H, s), 8.06 (1H, s).

Elem. Anal.: C₃₄H₃₇N₈O₁₀S₂Na.6.5H₂O.0.1NaHCO₃

Calcd.: C, 44.02; H, 5.43; N, 12.04; S, 6.89; Na, 2.72(%).

Found: C, 43.83; H, 5.45; N, 12.34; S, 6.81; Na, 2.70(%).

MS (m+1)=783.34

Example 125 Synthesis of Compound I-125

Step (1): Compound 125a→Compound 125b

A solution of Compound 125a (10.38 g, 45 mmol) in dichloromethane (100mL) was cooled with ice, and thereto was added dropwise boron tribromide(10.3 mL, 109 mmol). After stirring at 0° C. for 1 hour, the reactionmixture was poured to ice, and thereto was concentrated. Then theprecipitated solid was collected by filtration, so as to yield compound125b as a brown solid.

Yielded amount: 8.89 g, (98%)

¹H-NMR (DMSO-D₆) δ: 5.14 (2H, s), 6.92 (1H, s).

Step (2): Compound 125b→Compound 125c

To a solution of compound 125b (9.89 g, 49 mmol) in dimethylformamide(100 mL) was added potassium carbonate (20.44 g, 148 mmol),4-methoxybenzylchloride (16.12 mL, 118 mmol) and sodium iodide (7.39 g,49 mmol). After stirring at 50° C. for 1 hour, the reaction mixture waspoured to ice water. Then the precipitated solid was collected byfiltration, so as to yield compound 125c as a brown solid.

Yielded amount: 20.18 g, (93%)

¹H-NMR (CDCl₃) δ: 3.80 (3H, s), 3.84 (3H, s), 4.99 (2H, s), 5.13 (2H,s), 5.15 (2H, s), 6.82 (2H, d, J=8.66 Hz), 6.90 (1H, s), 6.94 (2H, d,J=8.66 Hz), 7.32 (2H, d, J=8.66 Hz), 7.36 (2H, d, J=8.66 Hz).

Step (3): Compound 125c→Compound 125d

To a solution of compound 125c (17.35 g, 39 mmol) in methanol (17 mL)and tetrahydrofuran (17 mL) was added 2 mol/L sodium hydroxide (59 mL,118 mmol) aqueous solution. After stirring at 70° C. for 1 hour, theretowas added ice water. Then the precipitated solid was collected byfiltration, so as to yield compound 125d as a white solid.

Yielded amount: 18.60 g, (98%)

¹H-NMR (DMSO-D₆) δ: 3.75 (3H, s), 3.77 (3H, s), 4.33 (2H, s), 4.81 (2H,s), 5.06 (2H, s), 5.85 (1H, s), 6.87 (2H, d, J=8.66 Hz), 6.96 (2H, d,J=8.66 Hz), 7.05 (1H, s), 7.33 (2H, d, J=8.66 Hz), 7.41 (2H, d, J=8.66Hz).

Step (4): Compound 125d→Compound 125e

A solution of Compound 125d (1.92 g, 4.0 mmol) in dichloromethane (15mL) and methanol (4 mL) was added manganese dioxide (3.47 g, 40 mmol).After stirring at room temperature for 1 hour, thereto was concentratedand added ethyl acetate. The insoluble substance was removed byfiltration. And thereto was added 1 mol/L hydrochloric acid aqueoussolution, followed by extraction with ethyl acetate twice time. Thecombined organic layer was washed with saturated brine, and then wasdried with anhydrous magnesium sulfate. The inorganic substance wasremoved by filtration, and then concentrated under reduced pressure.Thereto was added diisopropyl ether to precipitate a solid. The solidwas collected by filtration, so as to yield compound 125e as a whitesolid.

Yielded amount: 1.25 g (69%)

¹H-NMR (CDCl₃) δ: 3.80 (3H, s), 3.84 (3H, s), 4.96 (2H, dd, J=13.87,10.10 Hz), 5.14 (2H, dd, J=28.36, 11.04 Hz), 6.40 (1H, s), 6.81 (2H, d,J=8.53 Hz), 6.95 (2H, d, J=8.53 Hz), 7.06 (1H, s), 7.28 (2H, d, J=8.53Hz), 7.38 (2H, d, J=8.53 Hz).

Step (5): Compound 125e+Compound 122e→Compound 125f

A solution of Compound 125e (949 mg, 2.08 mmol) in dimethylacetamide(9.5 mL) was added Compound 122e (521 mg, 2.29 mmol) and sodium acetate(852 mg, 10.4 mmol). After stirring at room temperature for 1 hour,thereto was added acetic acid (0.594 ml, 10.4 mmol). After stirring at70° C. for over night, thereto was added ice water and 2 mol/L sodiumhydroxide aqueous solution until it gave a pH of 10.0 at 0° C. Theprecipitated solid was then collected by filtration and dissolvedtetrahydrofuran. The resultant solution was dried with anhydrous sodiumsulfate. The inorganic substance was removed by filtration, and thenconcentrated under reduced pressure. Thereto was added ethyl acetate toprecipitate a solid. The resulting crude product was purified by silicagel column chromatography (triethylamine/methanol/ethyl acetate), so asto yield compound 125f as a yellow solid.

Yielded amount: 435 mg (36%)

¹H-NMR (DMSO-D₆) δ: 1.46 (6H, t, J=7.53 Hz), 2.80 (6H, t, J=7.53 Hz),3.74 (4H, s), 3.79 (3H, s), 3.92 (2H, s), 4.97 (2H, s), 5.27 (2H, s),6.85 (2H, d, J=8.66 Hz), 7.01 (2H, d, J=8.66 Hz), 7.29 (2H, d, J=8.66Hz), 7.50 (2H, d, J=8.66 Hz), 7.67 (1H, s), 8.24 (1H, s).

Step (6): Compound X-24+Compound 125f→Compound I-125

From Compound X-24 (668 mg, 0.755 mmol) and Compound 125f (435 mg, 0.755mmol), Compound I-125 was obtained as a yellow powder using the samemethod as Example 120.

Yielded amount: 196 mg, (31%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.54 (3H, d, J=7.15 Hz),1.99 (6H, t, J=7.47 Hz), 3.39-3.55 (6H, m), 4.02-4.09 (4H, m), 4.61 (1H,d, J=14.31 Hz), 5.43 (1H, d, J=4.89 Hz), 5.83 (1H, d, J=4.89 Hz), 6.92(1H, s), 6.98 (1H, s), 7.94 (1H, s).

Elem. Anal.: C₃₄H₃₆ClN₈O₁₀S₂Na_(1.4).7.2H₂O

Calcd.: C, 41.75; H, 5.19; Cl, 3.62; N, 11.46; S, 6.56; Na, 3.29(%).

Found: C, 41.71; H, 5.15; Cl, 3.46; N, 11.73; S, 6.57; Na, 3.34(%).

MS (m+1)=817.42

Example 126 Synthesis of Compound I-126

Step (1): Compound 124b+Compound 126a→Compound 126b

From Compound 124b (20.65 g, 49 mmol) and Compound 126a (14.65 g, 68mmol), Compound 126b was obtained as a white powder using the samemethod as in Step (2) of Example 124.

Yielded amount: 19.57 g, (76%)

¹H-NMR (DMSO-D₆) δ: 1.14-1.19 (2H, m), 1.48-1.54 (2H, m), 2.19 (2H, s),2.39-2.45 (2H, m), 2.66-2.72 (2H, m), 3.75 (6H, s), 4.45 (2H, s), 5.20(2H, s), 5.23 (2H, s), 6.94-6.97 (4H, m), 7.38-7.43 (4H, m), 7.55 (1H,s), 7.72 (1H, s), 8.24 (1H, s).

Step (2): Compound X-24+Compound 126b→Compound I-126

From Compound X-24 (886 mg, 1.0 mmol) and Compound 126b (528 mg, 1.0mmol), Compound I-126 was obtained as a yellow powder using the samemethod as Example 120.

Yielded amount: 457 mg, (58%)

¹H-NMR (D₂O) δ: 1.49 (3H, s), 1.51 (3H, s), 1.53 (3H, d, J=7.15 Hz),2.00 (2H, s), 2.19 (2H, s), 3.37-3.66 (6H, m), 4.04 (1H, q, J=7.15 Hz),4.23 (1H, d, J=14.43 Hz), 4.48 (2H, dd, J=18.51, 14.62 Hz), 4.87 (1H, d,J=14.43 Hz), 5.34 (1H, d, J=4.89 Hz), 5.74 (1H, d, J=4.89 Hz), 6.96 (1H,s), 7.10 (1H, s), 7.43 (1H, s), 8.13 (1H, s).

Elem. Anal.: C₃₃H₃₅N₈O₁₀S₂Na.5.2H₂O

Calcd.: C, 44.81; H, 5.17; N, 12.67; S, 7.25; Na, 2.60(%).

Found: C, 44.77; H, 5.16; N, 12.77; S, 7.52; Na, 2.81(%).

MS (m+1)=769.48

Example 127 Synthesis of Compound I-127

Step (1): Compound X-1+Compound 127a→Compound I-127

From Compound X-1 (932 mg, 1.0 mmol) and Compound 127a (528 mg, 1.0mmol), Compound I-127 was obtained as a yellow powder using the samemethod as Example 120.

Yielded amount: 161 mg, (20%)

¹H-NMR (D₂O) δ: 1.46 (3H, t, J=7.22 Hz), 1.49 (3H, s), 1.52-1.53 (6H,m), 2.22-2.25 (4H, m), 3.36-3.39 (3H, m), 3.59-3.61 (1H, m), 4.12 (1H,q, J=6.90 Hz), 4.22-4.32 (3H, m), 4.44 (2H, s), 4.90 (1H, d, J=13.93Hz), 5.48 (1H, d, J=4.89 Hz), 5.83 (1H, d, J=4.89 Hz), 6.98 (1H, s),7.07 (1H, s), 7.53 (1H, s), 8.20 (1H, s).

Elem. Anal.: C₃₄H38N₇O₁₀S₂Na.8.1H₂O

Calcd.: C, 43.55; H, 5.83; N, 10.46; S, 6.84; Na, 2.45(%).

Found: C, 43.54; H, 5.85; N, 10.72; S, 6.58; Na, 2.48(%).

MS (m+1)=770.35

Example 128 Synthesis of Compound I-128

Step (1): Compound X-1+Compound 128a→Compound I-128

From Compound X-1 (932 mg, 1.0 mmol) and Compound 128a (530 mg, 1.0mmol), Compound I-128 was obtained as a yellow powder using the samemethod as Example 120.

Yielded amount: 331 mg, (42%)

¹H-NMR (D₂O) δ: 1.48-1.54 (12H, m), 2.25 (4H, s), 3.42-3.48 (2H, m),3.53-3.57 (1H, m), 3.74-3.76 (1H, m), 4.13 (1H, q, J=6.99 Hz), 4.40 (1H,d, J=14.43 Hz), 4.50 (2H, q, J=7.15 Hz), 4.60 (2H, s), 5.01 (1H, d,J=14.43 Hz), 5.48 (1H, d, J=4.77 Hz), 5.81 (1H, d, J=4.77 Hz), 6.99 (1H,s), 7.00 (1H, s), 7.33 (1H, s).

MS (m+1)=771.35

Example 129 Synthesis of Compound I-129

Step (1): Compound X-1+Compound 129a→Compound I-129

From Compound X-1 (932 mg, 1.0 mmol) and Compound 129a (563 mg, 1.0mmol), Compound I-129 was obtained as a yellow powder using the samemethod as Example 120.

Yielded amount: 246 mg, (30%)

¹H-NMR (D₂O) δ: 1.40 (3H, t, J=7.03 Hz), 1.50 (3H, s), 1.52 (3H, s),1.55 (3H, d, J=7.03 Hz), 2.23 (4H, d, J=10.42 Hz), 3.36 (3H, s), 3.56(1H, s), 4.11-4.23 (4H, m), 4.37 (2H, s), 4.89 (1H, d, J=14.18 Hz), 5.50(1H, d, J=4.89 Hz), 5.83 (1H, d, J=4.89 Hz), 6.87 (1H, s), 6.98 (1H, s),8.09 (1H, s).

Elem. Anal.: C₃₄H₃₇ClN₇O₁₀S₂Na.7.4H₂O

Calcd.: C, 42.56; H, 5.44; Cl, 3.69; N, 10.22; S, 6.68; Na, 2.40(%).

Found: C, 42.53; H, 5.39; Cl, 3.51; N, 10.41; S, 6.69; Na, 2.56(%).

MS (m+1)=804.33

Example 130 Synthesis of Compound I-130

Step (1): Compound X-24+Compound 130a→Compound I-130

From Compound X-24 (709 mg, 0.80 mmol) and Compound 130a (417 mg, 0.80mmol), Compound I-130 was obtained as a white powder using the samemethod as Example 120.

Yielded amount: 177 mg, (29%)

¹H-NMR (D₂O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.58 (3H, d, J=7.15 Hz),2.21-2.25 (4H, m), 3.46-3.97 (8H, m), 4.09 (1H, q, J=7.15 Hz), 4.26 (1H,d, J=14.31 Hz), 5.04 (1H, d, J=14.31 Hz), 5.47 (1H, d, J=4.77 Hz), 5.82(1H, d, J=4.77 Hz), 7.01 (1H, s), 7.12 (1H, s), 7.79 (1H, s).

MS (m+1)=733.35

Example 131 Synthesis of Compound I-131

Step (1): Compound 131a+Compound 131b→Compound 131c

To a solution of Compound 131a (4.57 g, 10.0 mmol) in methanol (45 mL)was added Compound 131b (877 mg, 10.5 mmol) and triethylamine (1.46 mL,10.5 mmol) at 00° C. After stirring at 00° C. for 1 hour, solvent wasremoved. The crude product was dissolved with ethyl acetate and washedwith water, aqueous hydrochloride and brine. The organic layer wasfiltered, dryed over magnesium sulfate and concentrated under reducedpressure to yield Compound 131c as brown oil. Compound 131c was used inthe next reaction without further purification.

Yielded amount: 4.86 g (100%)

¹H-NMR (CDCl₃) δ: 7.36 (2H, d, J=8.3 Hz), 7.32 (2H, d, J=8.6 Hz), 7.24(2H, s), 6.92 (2H, d, J=8.6 Hz), 6.82 (2H, d, J=8.6 Hz), 5.06 (2H, s),5.00 (2H, s), 4.09 (3H, s), 3.83 (3H, s), 3.80 (3H, s).

Step (2): Compound 131c+Compound 131d→Compound 131e

To a solution of Compound 131c (4.86 g, 10.0 mmol) in dimethylacetamide(40 mL) was added methanesulfonyl chloride (1.01 mL, 13.0 mmol) at −20°C. After the mixture was stirred at −20° C. for 30 minutes, the solutionof Compound 131d (1.96 g, 14.0 mmol) in dimethylacetamide (10 mL) wasadded to the mixture and the reaction mixture was stirred at 00° C. for30 minutes. Water and ethyl acetate were added to the reaction mixture,followed by extraction with ethyl acetate. The combined organic layerwas washed with water, aqueous hydrochloric acid solution and brine. Theorganic layer was filtered, dryed over magnesium sulfate andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography to yield Compound 131e as brown foam.

Yielded amount: 4.10 g (67%)

¹H-NMR (CDCl₃) δ: 7.36 (2H, d, J=8.1 Hz), 7.31 (2H, d, J=8.3 Hz),7.22-7.18 (2H, m), 6.92 (2H, t, J=8.6 Hz), 6.82 (2H, t, J=8.3 Hz), 5.94(1H, t, J=6.6 Hz), 5.03 (2H, s), 4.99 (2H, s), 4.01 (3H, s), 3.83 (3H,s), 3.79 (3H, s), 3.24 (2H, d, J=6.6 Hz), 2.95 (6H, t, J=7.5 Hz), 1.47(6H, t, J=7.3 Hz).

Step (3): Compound X-3+Compound 131e→Compound 131f→Compound I-131

To a solution of Compound X-3 (1.00 g, 1.26 mmol) in dimethylacetamide(2.0 mL) was added sodium iodide (377 mg, 2.56 mmo) and the mixture wasstirred at room temperature for 30 minutes. The mixture was cooled to 0°C. and then a solution of Compound 131e (766 mg, 1.26 mmol) indimethylacetamide (2.0 mL) was dropwised to it. The reaction mixture wasslowly added to 5% aqueous sodium chloride after stirring at 0° C. for 2hours. The precipitated solid was collected by filtration, washed withaqueous hydrochloride and water. The crude product Compound 131f wasdissolved into dichloromethane (12 mL) and the solution was dryed overmagnesium sulfate. Insoluble matter was removed by filtration to yieldCompound 131f as a solution of dichloromethane. Compound 131f was usedin the next reaction without further purification.

To a solution of Compound 131f in dichloromethane (12 mL) was addedanisole (1.37 mL, 12.6 mmol) and a 2 mol/L aluminum chloride solution(6.3 mL, 12.6 mmol) in nitromethane in turn at −20° C. To the reactionmixture were added diisopropyl ether and a small amount of water afterstirring at 0° C. for 30 minutes, and the resultant was stirred togenerate a precipitate. The supernatant was removed by decantation. Tothe insoluble matter adhering to the vessel were added a diluted aqueoushydrochloric acid solution, and acetonitrile. The resultant was stirredto dissolve the matter completely. Thereto was added HP20-SS resin.Acetonitrile was then distilled off therefrom under reduced pressure.The resultant mixed liquid was purified by ODS column chromatography.The desired-compound-containing fraction was concentrated under reducedpressure, and then freeze-dried to yield compound I-131 as a yellowpowder.

Yielded amount: 250 mg (24%)

¹H-NMR (D₂O) δ: 7.13 (1H, s), 7.06 (1H, s), 7.00 (1H, s), 5.84 (1H, d,J=4.5 Hz), 5.45 (1H, d, J=4.8 Hz), 4.65 (1H, d, J=14.4 Hz), 4.06 (2H, t,J=6.7 Hz), 3.99 (3H, s), 3.54-3.46 (6H, br m), 3.36 (2H, s), 1.92 (6H,s), 1.56 (3H, d, J=7.1 Hz), 1.52 (6H, d, J=7.6 Hz).

MS (m+1)=849.40

Example 132 Synthesis of Compound I-132

Step (1): Compound 132a+Compound 131b→Compound 132b

To a solution of Compound 132a (4.62 g, 10.0 mmol) in methanol (22 mL)and tetrahydrofuran (22 mL) was added Compound 131b (877 mg, 10.0 mmol)at 0° C. After stirring at 0° C. for 3 hour, solvent was removed. Thecrude product was dissolved with ethyl acetate and washed with water,aqueous hydrochloride and brine. The organic layer was filtered, dryedover magnesium sulfate and concentrated under reduced pressure to yieldCompound 132b as brown oil. Compound 132b was used in the next reactionwithout further purification.

Yielded amount: 2.77 g (59%)

¹H-NMR (CDCl₃) δ: 7.34 (2H, d, J=8.5 Hz), 7.29 (2H, d, J=8.7 Hz), 7.08(1H, s), 6.99 (1H, dd, J=10.9, 3.2 Hz), 6.91 (3H, d, J=8.7 Hz), 6.81(2H, d, J=8.7 Hz), 5.05 (2H, s), 5.04 (2H, s), 4.06 (3H, s), 3.83 (3H,s), 3.79 (3H, s).

Step (2): Compound 132b+Compound 131d→Compound 132c

From Compound 132b (2.77 g, 5.9 mmol) and Compound 131d (1.16 g, 8.3mmol), Compound 132c was obtained as a yellow foam using the same methodas in Step (2) of Example 131.

Yielded amount: 1.03 g (29%)

¹H-NMR (CDCl₃) δ: 7.33 (2H, d, J=8.6 Hz), 7.28 (2H, d, J=8.6 Hz), 7.10(1H, s), 7.01 (1H, dd, J=11.1, 1.5 Hz), 6.91 (2H, d, J=8.3 Hz), 6.81(2H, d, J=8.3 Hz), 5.96 (1H, s), 5.04 (2H, s), 5.01 (2H, s), 4.01 (3H,s), 3.82 (3H, s), 3.79 (3H, s), 3.21 (2H, d, J=6.3 Hz), 2.91-2.89 (6H,br m), 1.43-1.41 (6H, br m).

Step (3): Compound X-3+Compound 132c→Compound I-132

From Compound X-3 (1.0 g, 1.26 mmol) and Compound 132c (745 mg, 1.26mmol), Compound I-132 was obtained as a colorless powder using the samemethod as in Step (3) of Example 131.

Yielded amount: 314 mg (27%)

¹H-NMR (D₂O) δ: 7.01 (1H, s), 6.94 (1H, d, J=11.3 Hz), 6.91 (1H, s),5.85 (1H, d, J=4.8 Hz), 5.46 (1H, d, J=4.8 Hz), 4.65 (1H, d, J=14.4 Hz),4.07 (2H, t, J=7.5 Hz), 3.99 (3H, d, J=8.0 Hz), 3.50 (6H, t, J=18.1 Hz),3.37 (2H, s), 1.93 (6H, t, J=7.5 Hz), 1.57 (3H, d, J=7.2 Hz), 1.53 (3H,s), 1.51 (3H, s).

MS (m+1)=833.41

Example 133 Synthesis of Compound I-133

Step (1): Compound 131a+Compound 133a→Compound 133b

From Compound 131a (5.03 g, 11 mmol) and Compound 133a (1.62 g, 11mmol), Compound 133b was obtained as a brown oil using the same methodas in Step (1) of Example 131.

Yielded amount: 6.45 g (quant.)

¹H-NMR (CDCl₃) δ: 7.36-7.31 (5H, m), 7.17 (1H, d, J=7.3 Hz), 6.92 (2H,d, J=8.3 Hz), 6.82 (2H, d, J=8.3 Hz), 5.04 (2H, s), 5.00 (2H, s), 4.72(2H, s), 3.83 (3H, s), 3.80 (3H, s), 1.51 (9H, s).

Step (2): Compound 133b+Compound 131d→Compound 133c

From Compound 133b (6.45 g, 11 mmol) and Compound 131d (2.16 g, 15.4mmol), Compound 133c was obtained as a yellow foam using the same methodas in Step (2) Example 131.

Yielded amount: 5.42 g (70%)

¹H-NMR (CDCl₃) δ: 7.45-7.28 (6H, m), 7.18-7.16 (1H, m), 6.92 (2H, d,J=8.6 Hz), 6.81 (2H, d, J=8.8 Hz), 5.03 (2H, s), 4.97 (2H, s), 4.67 (2H,s), 3.83 (3H, s), 3.79 (3H, s), 3.26 (2H, d, J=6.3 Hz), 2.93 (6H, t,J=7.1 Hz), 1.48-1.43 (15H, br m).

Step (3): Compound X-3+Compound 133c→Compound I-133

From Compound X-3 (1.0 g, 1.26 mmol) and Compound 133c (892 mg, 1.26mmol), Compound I-133 was obtained as a yellow powder using the samemethod as in Step (3) Example 131.

Yielded amount: 260 mg (22%)

¹H-NMR (D₂O) δ: 7.15 (1H, s), 7.08 (1H, s), 7.01 (1H, s), 5.84 (1H, d,J=4.9 Hz), 5.46 (1H, d, J=4.8 Hz), 4.64 (1H, d, J=14.3 Hz), 4.57 (2H,s), 4.07 (2H, dd, J=10.5, 6.3 Hz), 3.49 (6H, t, J=19.1 Hz), 3.40 (3H,s), 1.95 (6H, t, J=7.6 Hz), 1.57 (3H, d, J=7.0 Hz), 1.52 (3H, s), 1.50(3H, s).

MS (m+1)=894.38

Example 134 Synthesis of Compound I-134

Step (1): Compound 131a+Compound 134a→Compound 134b

From Compound 131a (4.57 g, 10 mmol) and Compound 134a (3.03 g, 11mmol), Compound 134b was obtained as a brown oil using the same methodas in Step (1) of Example 131.

Yielded amount: 7.1 g (99%)

¹H-NMR (CDCl₃) δ: 7.49 (1H, d, J=1.8 Hz), 7.36-7.27 (20H, m), 6.88 (2H,d, J=8.6 Hz), 6.83 (2H, d, J=8.3 Hz), 5.06 (2H, s), 4.98 (2H, s), 3.81(3H, s), 3.79 (3H, s).

Step (2): Compound 134b+Compound 131d→Compound 134c

From Compound 134b (7.1 g, 9.9 mmol) and Compound 131d (1.95 g, 13.9mmol), Compound 134c was obtained as a brown oil using the same methodas in Step (2) of Example 131.

Yielded amount: 1.67 g (20%)

¹H-NMR (CDCl₃) δ: 7.41-7.26 (29H, m), 6.86 (2H, d, J=8.3 Hz), 6.82 (2H,d, J=8.3 Hz), 6.31 (1H, t, J=6.3 Hz), 5.02 (2H, d, J=5.6 Hz), 4.95 (2H,d, J=8.6 Hz), 3.82 (3H, s), 3.78 (3H, s), 2.98 (2H, d, J=6.3 Hz), 2.83(6H, t, J=7.3 Hz), 1.15 (6H, t, J=7.3 Hz).

Step (3): Compound X-3+Compound 134c→Compound I-134

From Compound X-3 (1.0 g, 1.26 mmol) and Compound 134c (1.05 g, 1.26mmol), Compound I-134 was obtained as a colorless powder using the samemethod as in Step (3) of Example 131.

Yielded amount: 390 mg (28%)

¹H-NMR (D₂O) δ: 7.13 (1H, d, J=1.9 Hz), 7.01 (1H, s), 6.98 (1H, d, J=2.0Hz), 5.84 (1H, d, J=4.9 Hz), 5.44 (1H, d, J=4.9 Hz), 4.64 (1H, d, J=14.4Hz), 4.06 (2H, q, J=7.3 Hz), 3.54-3.39 (6H, m), 3.31 (2H, s), 1.91 (6H,t, J=7.8 Hz), 1.56 (3H, d, J=7.0 Hz), 1.53 (3H, s), 1.51 (3H, s).

MS (m+1)=835.42

Example 135 Synthesis of Compound I-135

Step (1): Compound 132a+Compound 133d→Compound 3bb135a

To a solution of Compound 132a (4.99 g, 10.8 mmol) and aqueoushydrochloric acid (5.4 mL, 10.8 mmol) in methanol (25 mL) andtetrahydrofuran (25 mL) was added Compound 133d (1.77 g, 12.0 mmol) at0° C. After stirring at 0° C. for 3 hour, solvent was removed. The crudeproduct was dissolved with ethyl acetate and washed with water, aqueoushydrochloric acid and brine. The organic layer was filtered, dryed overmagnesium sulfate and concentrated under reduced pressure to yieldCompound 135a as brown oil. Compound 135a was used in the next reactionwithout further purification.

Yielded amount: 4.41 g (65%)

¹H-NMR (CDCl₃) δ: 7.34 (2H, d, J=8.1 Hz), 7.29 (2H, t, J=7.7 Hz), 7.11(2H, t, J=13.0 Hz), 6.92 (3H, t, J=8.0 Hz), 6.82 (2H, d, J=8.3 Hz), 5.05(2H, s), 5.03 (2H, s), 4.71 (2H, s), 3.83 (3H, s), 3.78 (3H, s), 1.51(9H, s).

Step (2): Compound 135a+Compound 131d→Compound 135b

From Compound 135b (4.41 g, 6.5 mmol) and Compound 131d (1.27 g, 9.1mmol), Compound 135b was obtained as a yellow foam using the same methodas in Step (2) of Example 131.

Yielded amount: 2.73 g (62%)

¹H-NMR (CDCl₃) δ: 7.33 (2H, d, J=8.5 Hz), 7.29 (2H, d, J=8.8 Hz), 7.14(1H, s), 7.04 (1H, dd, J=11.0, 6.5 Hz), 6.91 (2H, dd, J=5.5, 3.1 Hz),6.81 (2H, d, J=8.7 Hz), 5.04 (2H, s), 5.01 (2H, s), 4.66 (2H, s), 3.83(3H, s), 3.79 (3H, s), 3.29 (2H, d, J=6.4 Hz), 3.03-2.97 (6H, m), 1.60(6H, m), 1.48 (9H, s).

Step (3): Compound X-3+Compound 135b→Compound I-135

From Compound X-3 (1.0 g, 1.26 mmol) and Compound 135b (853 mg, 1.26mmol), Compound I-135 was obtained as a yellow powder using the samemethod as in Step (3) of Example 131.

Yielded amount: 175 mg (15%)

¹H-NMR (D₂O) δ: 7.01 (1H, s), 6.98-6.96 (2H, m), 5.84 (1H, d, J=4.8 Hz),5.46 (1H, d, J=4.9 Hz), 4.64 (2H, d, J=13.9 Hz), 4.57 (2H, s), 4.08-4.06(2H, m), 3.52-3.47 (6H, m), 3.40 (2H, s), 1.95 (6H, t, J=7.7 Hz), 1.57(3H, s), 1.52 (3H, s), 1.50 (3H, d, J=5.8 Hz).

MS (m+1)=877.52

Example 136 Synthesis of Compound I-136

Step (1): Compound 132a+Compound 136a→Compound 136b

From Compound 132a (4.99 g, 10 mmol) and Compound 136a (1.90 g, 10mmol), Compound 136b was obtained as a brown oil using the same methodas in Step (1) of Example 132.

Yielded amount: 5.11 g (89%) ¹H-NMR (CDCl₃) δ: 7.32 (2H, d, J=8.5 Hz),7.29 (2H, d, J=8.5 Hz), 7.11 (OH, d, J=188.6 Hz), 7.05 (1H, s), 6.98(1H, dd, J=11.1, 1.6 Hz), 6.92-6.89 (4H, m), 6.81 (2H, d, J=8.7 Hz),5.22 (2H, s), 5.05 (2H, s), 5.03 (2H, s), 3.83 (3H, s), 3.81 (3H, s),3.79 (3H, s).

Step (2): Compound 136b+Compound 131d→Compound 136c

From Compound 136a (5.11g, 8.9 mmol) and Compound 136a (1.75 g, 12.5mmol), Compound 136b was obtained as a yellow foam using the same methodas in Step (2) of Example 131.

Yielded amount: 2.4 g (39%)

¹H-NMR (CDCl₃) δ: 7.34-7.32 (4H, m), 7.29 (2H, d, J=8.5 Hz), 7.12 (1H,s), 7.03 (1H, dd, J=11.0, 1.8 Hz), 6.91 (4H, d, J=8.7 Hz), 6.81 (2H, d,J=8.5 Hz), 5.91 (1H, t, J=6.4 Hz), 5.15 (2H, s), 5.04 (2H, s), 5.03 (2H,s), 3.83 (3H, s), 3.82 (3H, s), 3.79 (3H, s), 3.14 (2H, d, J=6.5 Hz),2.75-2.73 (6H, br m), 1.29-1.24 (6H, m).

Step (3): Compound X-3+Compound 136c→Compound I-136

From Compound X-3 (1.0 g, 1.26 mmol) and Compound 136c (878 mg, 1.26mmol), Compound I-136 was obtained as a colorless powder using the samemethod as in Step (3) of Example 131.

Yielded amount: 400 mg (40%)

¹H-NMR (D₂O) δ: 7.00 (1H, s), 6.95 (1H, d, J=11.3 Hz), 6.92 (1H, s),5.84 (1H, d, J=4.9 Hz), 5.45 (1H, d, J=4.8 Hz), 4.64 (1H, d, J=14.2 Hz),4.06 (2H, t, J=7.0 Hz), 3.51-3.47 (6H, br m), 3.39 (3H, s), 1.96-1.94(6H, br m), 1.56 (3H, d, J=7.0 Hz), 1.54 (3H, s), 1.50 (3H, s).

MS (m+1)=819.54

Example 137 Synthesis of Compound I-137

Step (1): Compound 137a+Compound 134a→Compound 137b

From Compound 137a (4.39 g, 9.60 mmol) and Compound 134a (2.64 g, 9.60mmol), Compound 137b was obtained as a brown oil using the same methodas in Step (1) of Example 131.

Yielded amount: 2.57 g (38%)

¹H-NMR (CDCl₃) δ: 7.51-7.43 (19H, m), 6.94-6.89 (2H, m), 6.82-6.79 (2H,m), 5.09-4.95 (4H, m), 3.84-3.74 (6H, m).

Step (2): Compound 137b+Compound 137c→Compound 137d

From Compound 3cc (2.57 g, 3.60 mmol) and Compound 7 (545 mg, 4.32mmol), Compound 3cc was obtained as a brown oil using the same method asin Step (2) of Example 131.

Yielded amount: 940 mg (32%)

¹H-NMR (CDCl₃) δ: 7.34 (7H, dt, J=25.1, 7.5 Hz), 7.23 (13H, br s), 6.93(2H, d, J=8.3 Hz), 6.77 (2H, d, J=8.3 Hz), 5.11 (2H, s), 4.98 (2H, s),3.84 (3H, s), 3.73 (3H, s), 3.36 (2H, d, J=5.3 Hz), 2.99-2.79 (6H, m),1.82-1.64 (6H, br m).

Step (3): Compound X-3+Compound 137d→Compound I-137

To a solution of Compound X-3 (908 mg, 1.14 mmol) in dimethylacetamide(2.0 mL) was added sodium iodide (342 mg, 2.29 mmo) and the mixture wasstirred at room temperature for 30 minutes. The mixture was cooled to 0°C. and then a solution of Compound 137d (800 mg, 1.14 mmol) indimethylacetamide (2.0 mL) was dropwised to it. The reaction mixture wasslowly added to 5% aqueous sodium chloride after stirring at 0° C. for 2hours. The precipitated solid was collected by filtration, washed withaqueous hydrochloride and water and suspended into water. The suspensionwas freeze-dried to yield the crude product as a brown solid. The crudeproduct yielded was used as it was, without being purified, in the nextreaction.

To a solution of the crude product in dichloromethane (12 mL) was addedanisole (1.25 mL, 11.4 mmol) and a 2 mol/L aluminum chloride solution(5.7 mL, 11.4 mmol) in nitromethane in turn at −20° C. To the reactionmixture were added diisopropyl ether and a small amount of water afterstirring at 0° C. for 30 minutes, and the resultant was stirred togenerate a precipitate. The supernatant was removed by decantation. Tothe insoluble matter adhering to the vessel were added a diluted aqueoushydrochloric acid solution, and acetonitrile. The resultant was stirredto dissolve the matter completely. Thereto was added HP20-SS resin.Acetonitrile was then distilled off therefrom under reduced pressure.The resultant mixed liquid was purified by ODS column chromatography.The desired-compound-containing fraction was concentrated under reducedpressure, and then freeze-dried to yield compound I-137 as a yellowpowder.

Yielded amount: 280 mg (29%)

¹H-NMR (D₂O) δ: 7.05-6.97 (3H, m), 5.87-5.86 (1H, m), 5.46-5.45 (1H, m),4.31-4.07 (5H, m), 3.81-3.51 (7H, m), 2.36-2.31 (4H, m), 1.59 (3H, d,J=6.9 Hz), 1.53 (3H, s), 1.51 (3H, s).

Example 138 Synthesis of Compound I-138

Step (1): Compound 138a+Compound 136a→Compound 138b

To a solution of Compound 138a (5.58 g, 10.0 mmol) in methanol (45 mL)was added acetic acid (0.572 mL, 10.0 mmol), Compound 136a (1.90 g, 10.0mmol) and triethylamine (1.39 mL, 10.0 mmol) at 0° C. After stirring at0° C. for 1 hour, solvent was removed. The crude product was dissolvedwith ethyl acetate and washed with water, aqueous hydrochloride andbrine. The organic layer was filtered, dryed over magnesium sulfate andconcentrated under reduced pressure to yield Compound 138b as brown oil.Compound 138b was used in the next reaction without furtherpurification.

Yielded amount: 5.92 g (100%)

¹H-NMR (CDCl₃) δ: 7.36-7.31 (6H, m), 7.21 (2H, s), 6.92-6.90 (4H, m),6.82 (2H, d, J=8.7 Hz), 5.23 (2H, s), 5.04 (2H, s), 4.99 (2H, s), 3.83(3H, s), 3.81 (3H, s), 3.80 (3H, s).

Step (2): Compound 138b+Compound 137c→Compound 138c

From Compound 138b (1.78 g, 3.0 mmol) and Compound 137c (492 mg, 3.9mmol), Compound 138c was obtained as a yellow foam using the same methodas in Step (2) of Example 131.

Yielded amount: 800 mg (38%)

¹H-NMR (CDCl₃) δ: 7.38-7.30 (6H, m), 7.23 (1H, d, J=5.1 Hz), 7.16 (1H,t, J=4.3 Hz), 6.91-6.84 (6H, m), 5.15 (2H, s), 5.08-5.06 (2H, m),5.02-5.00 (2H, m), 4.70 (1H, br s), 3.83-3.77 (9H, m), 3.29-2.55 (8H,m), 1.92-1.73 (3H, m), 1.22-1.17 (2H, m).

Step (3): Compound X-3+Compound 138c→Compound I-138

From Compound X-3 (908 mg, 1.14 mmol) and Compound 138c (800 mg, 1.14mmol), Compound I-138 was obtained as a white powder using the samemethod as in Step (3) of Example 137.

Yielded amount: 320 mg (33%, E/Z=29:64 or 64:29)

¹H-NMR (D₂O) δ: 7.11-7.09 (2H, m), 7.00 (1H, s), 5.85-5.84 (1H, m), 5.44(1H, s), 4.87 (2H, t, J=27.9 Hz), 4.32 (1H, t, J=15.0 Hz), 4.13-4.05(2H, m), 3.81-3.67 (7H, br m), 2.37 (4H, s), 1.59-1.56 (3H, m), 1.52(3H, s), 1.50 (3H, s).

MS (m+1)=822.5

Example 139 Synthesis of Compound I-139

Step (1): Compound 139a+Compound 137c→Compound 139b

From Compound 139a (2.88 g, 5.0 mmol) and Compound 137c (757 mg, 6.0mmol), Compound 139b was obtained as a yellow foam using the same methodas Step (2) of in Step (2) of Example 131.

Yielded amount: 861 mg (25%)

¹H-NMR (CDCl₃) δ: 7.34-7.27 (8H, m), 6.90-6.88 (4H, m), 6.82 (2H, d,J=8.6 Hz), 5.14 (2H, s), 5.09-5.00 (4H, m), 4.69 (1H, s), 3.82-3.80 (9H,m), 3.27-3.18 (2H, br m), 3.08-2.82 (4H, m), 2.81-2.70 (2H, m),2.60-2.53 (1H, m), 2.03-1.70 (3H, m), 1.42 (1H, br s).

Step (2): Compound X-3+Compound 139b→Compound I-139

From Compound X-3 (1.0 g, 1.26 mmol) and Compound 139b (861 mg, 1.26mmol), Compound I-139 was obtained as a colorless powder using the samemethod as in Step (3) of Example 137.

Yielded amount: 320 mg (31%, E/Z or Z/E=34:63)

¹H-NMR (D₂O) δ: 7.00 (1H, s), 6.96 (2H, d, J=11.7 Hz), 5.86-5.84 (1H,m), 5.45-5.44 (1H, m), 4.33 (2H, t, J=14.7 Hz), 4.13-4.07 (2H, m),3.87-3.49 (8H, m), 2.38-2.36 (4H, br m), 1.59-1.57 (3H, m), 1.52 (3H,s), 1.50 (3H, s).

MS (m+1)=805.82

Example 140 Synthesis of Compound I-140

Step (1): Compound X-24+Compound 140a→Compound 140b→Compound I-140

Compound X-24 (886 mg, 1.0 mmol) and compound 140a (397 mg, 1.0 mmol)which was synthesized into according to the synthesis in WO2011125966A1were used to synthesize the target compound in the same way as in Step(4) of Example 107.

Yielded amount: 334.2 mg, (37%)

¹H-NMR (D₂O) δ: 7.78 (1H, s), 7.12 (1H, s), 7.00 (1H, s), 5.84 (1H, d,J=4.9 Hz), 5.45 (1H, d, J=4.9 Hz), 4.64 (1H, d, J=14.3 Hz), 4.11-4.05(2H, m), 3.58-3.42 (6H, m), 3.39 (2H, s), 1.94 (6H, t, J=7.8 Hz), 1.56(3H, d, J=7.2 Hz), 1.52 (3H, s), 1.50 (3H, s).

Elem. Anal.: C32H37N8O10S2Na(H2O) 6.1

Calcd.: C, 43.15; H, 5.57; N, 12.58; S, 7.20; Na, 2.58(%).

Found: C, 43.10; H, 5.45; N, 12.82; S, 7.21; Na, 2.64(%).

Example 141 Synthesis of Compound I-141

Step (1): Compound 141a→Compound 141b

To a cooled (0° C.) solution of compound 141a (17.4 g, 30.0 mmol) in DMA(200 ml) was added 39% peraceticacid (5.69 ml, 33.0 mmol) After stirringfor 1 hr at 0° C., the mixture was quenched by 50 mL of 10% sodiumbisulfite aqueous solution. The resulting solid was collected byfiltration and washed with water and isopropanol to afford 17.4 g ofcompound 141b (98%).

¹H-NMR (DMSO-D₆) δ: 8.57 (d, J=8.1 Hz, 1H), 7.50 (d, J=7.7 Hz, 2H),7.42-7.21 (m, 13H), 6.97 (s, 1H), 5.91 (dd, J=8.1, 4.5 Hz, 1H), 5.03 (d,J=4.5 Hz, 1H), 4.20 (d, J=18.1 Hz, 1H), 4.01 (d, J=18.1 Hz, 1H), 3.69(d, J=14.0 Hz, 1H), 3.55 (d, J=14.0 Hz, 1H), 3.12 (s, 3H).

Step (2): Compound 141b→Compound 141c

To a solution of compound 141b (17 g, 28.6 mmol) in DMF (170 ml) wasadded dimethylamine hydrochloride (2.33 g, 28.6 mmol) and 36% 38%formalin (4.26 ml, 57.2 mmol). After stirring for 30 min at 50° C., theresulting mixture was poured into water then the resulting solid wascollected by filtration to afford 13.2 g of compound 141c (76%)

¹H-NMR (DMSO-D₆) δ: 8.59 (d, J=8.3 Hz, 1H), 7.53 (d, J=7.7 Hz, 2H),7.42-7.23 (m, 14H), 6.95 (s, 1H), 6.51 (s, 1H), 6.45 (s, 1H), 6.05 (dd,J=8.3, 5.0 Hz, 1H), 5.25 (d, J=5.0 Hz, 1H), 3.69 (d, J=14.1 Hz, 1H),3.58 (d, J=14.1 Hz, 1H), 3.23 (s, 3H).

Step (3): Compound 141c→Compound 141d

To a cooled (−40° C.) solution of sodium borohydride (937 mg, 24.8 mmol)in MeOH (300 ml) was added dropwise a solution of compound 141c (12.5 g,20.6 mmol) in 250 ml of THF under −40° C. After the mixture was stirredat −40° C. for 30 min, TFA (0.163 ml, 2.12 mmol) was added. Then themixture was concentrated in vacuo. The resulting precipitate wascollected by filtration and washed by MeOH to afford 9.40 g of compound141d (75%).

¹H-NMR (DMSO-D₆) δ: 8.61 (d, J=8.1 Hz, 1H), 7.49 (d, J=7.7 Hz, 2H),7.44-7.22 (m, 13H), 6.95 (s, 1H), 5.94 (dd, J=3.5, 8.1 Hz, 1H), 5.18 (d,J=3.5 Hz, 1H), 4.06 (q, J=7.7 Hz, 1H), 3.68 (d, J=14.3 Hz, 1H), 3.57 (d,J=14.3 Hz, 1H), 3.04 (s, 3H), 1.55 (d, J=7.7 Hz, 3H).

Step (4): Compound 141d→Compound 141e

To a cooled (−40° C.) solution of compound 141d (9.39 g, 15.4 mmol) inDMF (100 ml) was added phosphorous tribromide (1.75 ml, 18.5 mmol).After the reaction mixture was stirred for 15 min at −40° C., themixture was diluted with water. The resulting solid was collected byfiltration and washed by water to afford 9.40 g of compound 141e.

¹H-NMR (DMSO-D₆) δ: 9.22 (d, J=8.4 Hz, 1H), 7.48 (d, J=7.8 Hz, 2H),7.42-7.19 (m, 13H), 6.90 (s, 1H), 5.83 (dd, J=8.4, 5.0 Hz, 1H), 5.41 (d,J=5.0 Hz, 1H), 4.26 (q, J=7.1 Hz, 1H), 3.60-3.50 (m, 2H), 3.07 (s, 3H),1.48 (d, J=7.1 Hz, 3H).

Step (5): Compound 141e→Compound 141f

To a cooled (−20° C.) slurry of phosphorus pentachloride (4.01 g, 19.2mmol) in dichloromethane (60.0 ml) was added pyridine (1.67 ml, 21.2mmol) followed by compound 141e (5.7 g, 9.62 mmol). After the mixturewas stirred for 45 min at 0° C., the mixture was cooled to −40° C. thenMeOH (23.4 ml, 577 mmol) was added to this mixture in one portion. Themixture was warmed to room temperature and diluted with water anddichloromethane. The aqueous layer was extracted with dichloromethane.The combined organic layers were washed with water and brine, dried overMgSO₄, filtered. To this mixture was added 4 mmol/l HCl in EtOAc (3.61ml) then this solution was concentrated in vaqcuo. The resulting residuecompound 141f was used in next Step without further purification.

Step (6): Compound 141f+Compound 141g→Compound 141h

To a cooled (−50° C.) solution of compound 141f (9.62 mmol) in dichloromethane (50.0 ml) were added compound 141g (4.96 g, 11.5 mmol) andphenyl dichlorophosphate (1.87 ml, 12.5 mmol) followed by N-methylmorpholine (4.23 ml, 38.5 mmol). After 1 hr at −50° C., the reactionmixture was poured into water. Then the aqueous layer was extracted withethyl acetate and the combined extracts were washed with water andbrine, dried (MgSO4), filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography to afford 1.25 g of compound141h (25%).

¹H-NMR (CDCl₃) δ: 8.29 (d, J=9.0 Hz, 1H), 7.42-7.28 (m, 11H), 6.94 (s,1H), 6.06 (dd, J=9.0, 5.1 Hz, 1H), 5.29 (d, J=5.0 Hz, 1H), 4.15-4.02 (m,1H), 2.62 (s, 3H), 1.63 (d, J=10.0 Hz, 3H), 1.52 (s, 15H), 1.41 (s, 9H).

Step (7): Compound 141h→Compound 141i

To a cooled (0° C.) solution of compound 141h (4.93 g, 5.57 mmol) intetrahydrofuran (50.0 ml) were added magnesium bromide diethyl etherate(7.19 g, 27.9 mmol), pyridine-4-thiol (1.36 g, 12.3 mmol) and potassiumcarbonate (1.69 g, 12.3 mmol). After stirring for 2 hr at 00° C., thereaction mixture was poured into water. Then the aqueous layer wasextracted with ethyl acetate and the combined extracts were washed withwater and brine, dried (MgSO4), filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography to afford 1.25 g ofcompound 5i (25%).

¹H-NMR (CDCl3) δ: 8.39-8.32 (m, 1H), 7.44-7.21 (m, 13H), 7.08 (d, J=5.9Hz, 2H), 6.98 (s, 1H), 6.05 (dd, J=8.8, 5.1 Hz, 1H), 5.38 (d, J=5.1 Hz,1H), 3.82 (q, J=7.2 Hz, 1H), 1.63 (d, J=9.7 Hz, 6H), 1.53 (s, 9H), 1.42(s, 9H).

Step (8): Compound 141i+Compound 141j→Compound 141k

To a cooled (00° C.) solution of compound 141i (0.90 g, 1.00 mmol) inDMF (3.00 ml) was added compound 141j (0.56 g, 1.10 mmol; ref.WO2013002215A1). After stirring overnight at 0° C., the reaction mixturewas poured into water. Then the aqueous layer was extracted with ethylacetate and the combined extracts were washed with water and brine,dried (MgSO4), filtered, and concentrated in vacuo. The resultingresidue compound 141k was used in next Step without furtherpurification.

Step (9): Compound 141k→Compound I-141

To a cooled (−20° C.) solution of compound 141k in dichloromethane (15.0ml) was added anisole (1.09 ml, 10.0 mmol) followed by 2 mol/L aluminumchloride solution (5.00 mL, 10.0 mmol) in nitromethane in one portion.After stirring for 30 min at −20° C., the mixture was quenched withwater (15.0 ml). The resulting precipitate was dissolved in 2 mol/Laqueous hydrochloric acid solution and acetonitrile. The water phase waswashed with diisopropyl ether. To this water phase was added HP20SSresin and involved acetonitrile was distilled off under reducedpressure. The residual suspension was loaded HP20SS precolum connectedODS column and purified. To the resultant target-compound solution wasadded a 0.2 mol/L aqueous sodium hydroxide solution until the whole gavea pH of 6.0. Then a piece of dry ice was added thereto. The resultantsolution was concentrated under reduced pressure, and then freeze-driedto afford 508 mg of compound I-141 (65% from compound 141i)

¹H-NMR (D₂O) δ: 8.38 (d, J=6.6 Hz, 2H), 7.87 (d, J=6.6 Hz, 2H), 7.53 (d,J=8.6 Hz, 1H), 6.99 (s, 1H), 6.93 (d, J=8.6 Hz, 1H), 5.85 (d, J=5.1 Hz,1H), 5.65 (d, J=5.1 Hz, 1H), 4.22 (q, J=7.2 Hz, 1H), 1.54-1.50 (m, 9H).

Elemental Analysis: C30H26ClN6NaO10S3(H2O) 5

Calcd.: C, 41.17; H, 4.15; N, 9.60; S, 10.99; Cl, 4.05; Na, 2.63(%).

Found: C, 40.88; H, 4.16; N, 9.72; S, 11.00; Cl, 4.26; Na, 2.93(%).

Example 142 Synthesis of Compound I-142

Step (1): Compound 142a→Compound 142b

Compound 142a (12.8 g, 30.0 mmol) was used to synthesized the compound142b in the same way as in Step (1) of example 117.

Yielded amount: 14.1 g, (86%)

¹H-NMR (CDCl₃) δ: 8.11 (d, J=8.6 Hz, 1H), 7.97 (s, 1H), 7.74 (s, 1H),7.60-7.53 (m, 1H), 7.49-7.43 (m, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.33 (d,J=8.3 Hz, 2H), 6.94 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 5.17 (s,2H), 5.14 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H).

Step (2): Compound 142b→Compound 142c

Compound 142b (1.63 g, 3.00 mmol) was used to synthesized the compound142c in the same way as in Step (2) of example 117.

Yielded amount: 1.53 g (95%)

¹H-NMR (CDCl₃) δ: 7.41 (d, J=1.6 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.32(d, J=8.5 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.09(t, J=5.8 Hz, 1H), 5.10 (s, 2H), 5.03 (s, 2H), 3.83 (s, 3H), 3.80 (s,3H), 3.78 (d, J=6.3 Hz, 2H), 3.04-2.92 (m, 2H), 2.66-2.60 (m, 2H), 2.34(s, 2H), 1.35-1.22 (m, 2H).

Step (3): Compound 142c+Compound X-24→Compound I-142

Compound X-24 (0.886 g, 1.00 mmol) and compound 142c (0.537 g, 1.00mmol) were used to synthesized the target compound in the same way as inStep (4) of example 107.

Yidlded amount: 0.291 g (36%)

¹H-NMR (D₂O) δ: 7.38 (d, J=1.8 Hz, 1H), 7.22 (d, J=1.8 Hz, 1H), 6.99 (s,1H), 5.77 (d, J=4.7 Hz, 1H), 5.40 (d, J=4.7 Hz, 1H), 4.90 (d, J=14.4 Hz,1H), 4.24 (d, J=14.4 Hz, 1H), 4.04 (q, J=7.1 Hz, 1H), 3.74-3.51 (m, 6H),3.41 (d, J=8.5 Hz, 1H), 3.31 (d, J=8.5 Hz, 1H), 2.29-2.15 (m, 2H),2.02-1.92 (m, 2H), 1.55 (d, J=7.1 Hz, 3H), 1.52-1.48 (m, 6H).

Elemental Analysis: C32H35ClN7NaO10S2(H2O) 6.4

Calcd.: C, 41.98; H, 5.26; N, 10.71; Cl, 3.87; Na, 2.51(%).

Found: C, 41.94; H, 5.16; N, 10.87; Cl, 3.72; Na, 2.61(%).

Example 143 Synthesis of Compound I-143 Step (1): Compound X-24→Compound143a)

Compound 143a:1-((6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-1-(((4S,6R,7R)-7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((4-methoxybenzyl)oxy)carbonyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)pyrrolidin-1-ium,Iodide

6,7-bis((4-methoxybenzyl)oxy)-1-methyl-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one(WO2013052568A1 0.588 g, 1.14 mmol) in DMF (5 mL) at 0° C. undernitrogen was added compound X-24 (1.063 g, 1.200 mmol) (in DMF (5 mL).The mixture was stirred at the same temperature over 3 h, and was leftin a freezer overnight. The solution was poured into ice-cooled 5% NaClaq (100 mL) containing NaHSO₃ (1 g) and was stirred for 15 min. Thesolid was collected by filtration, washed with water and dried, andpurified by automated silica gel chromatography (Combiflash RF), elutingwith MeOH/DCM (0-20%) to afford compound 143a (0.269 g, 15% yield) as abrown solid. LCMS: (M+H)⁺: 1273.5.

Step (2): Compound 143a→Compound I-143

Compound I-143:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

Compound 143a (0.269 g, 0.142 mmol) in DCM (1.5 mL) at 0° C. was addedanisole (0.16 mL, 1.42 mmol), followed by TFA (0.50 mL, 6.5 mmol). Themixture was warmed up to rt and then stirred overnight. Diisopropylether (30 mL) was added, and the mixture was stirred for 10 min. Theresulting precipitate was collected by filtration, and washed twice withdiisopropyl ether (2×5 mL). The solid was dissolved in a mixture of MeCN(6 mL), water (6 mL), and 2 M HCl aq (1.5 mL), and HP20SS resin (6 g)was added. The mixture was concentrated to dryness, and the resin wasloaded onto a pre-column containing HP20SS resin (10 g), and purified byautomated reverse phase chromatography eluting with 0-20% MeCN/water toafford

(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(67 mg, 62% yield) as an off-white solid. A portion of this product (56mg, 0.074 mmol) was suspended in water (HPLC grade, 10 mL) and cooled to0° C. To the vigorously stirring suspension was added 0.1 N NaOH aq(0.74 mL, 0.074 mmol) slowly using an Eppendorf pipette. After theaddition was complete, a small piece of dry ice was added to quench anyextra NaOH. The pale yellow solution was then frozen and lyophilized toafford compound I-143 (57 mg) as an off-white solid.

LCMS: (M+H)⁺: 756.2. ¹H NMR (400 MHz, D₂O) δ ppm 1.32-1.43 (m, 9H) 2.10(d, J=10.86 Hz, 4H) 3.25 (br. s., 3H) 3.48 (br. s., 1H) 3.80 (s, 3H)4.00 (d, J=6.57 Hz, 1H) 4.11 (d, J=14.40 Hz, 1H) 4.33 (s, 2H) 4.78-4.81(m, 1H) 5.35 (d, J=4.80 Hz, 1H) 5.70 (d, J=4.80 Hz, 1H) 6.87 (s, 1H)6.96 (s, 1H) 7.48 (s, 1H) 8.05 (s, 1H).

The compounds shown below were obtained from Compound X-24 and the eachcorresponding amine which was synthesized according to the synthesis inWO2013052568A1 in the same way as example 143.

Example 144 Synthesis of Compound I-144

Compound I-144:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((1-ethyl-5-fluoro-6,7-dihydroxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 788.1. ¹H NMR (400 MHz, D₂O) δ ppm 1.24-1.48 (m, 12H)1.99-2.23 (m, 4H) 3.22 (br. s., 3H) 3.46 (d, J=3.28 Hz, 1H) 3.96-4.17(m, 4H) 4.27 (br. s., 2H) 4.79 (d, J=7.33 Hz, 1H) 5.35 (d, J=4.80 Hz,1H) 5.70 (d, J=4.80 Hz, 1H) 6.70 (s, 1H) 6.85 (s, 1H) 8.03 (s, 1H).

Example 145 Synthesis of Compound I-145

Compound I-145:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((5-chloro-6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 790.0. ¹H NMR (400 MHz, D₂O) δ ppm 1.27-1.50 (m, 9H) 2.08(br. s., 4H) 3.21 (d, J=6.32 Hz, 3H) 3.45 (br. s., 1H) 3.63 (br. s., 3H)3.95-4.12 (m, 2H) 4.21 (br. s., 2H) 4.78 (d, J=11.62 Hz, 1H) 5.36 (d,J=4.80 Hz, 1H) 5.70 (d, J=4.80 Hz, 1H) 6.65 (br. s., 1H) 6.85 (s, 1H)7.91 (br. s., 1H).

Example 146 Synthesis of Compound I-146

Step (1): 6,7-dimethoxyquinazolin-4(3H)-one→Compound 146a

Compound 146a: 3-(2-chloroethyl)-6,7-dimethoxyquinazolin-4 (3H)-one

To a solution of 6,7-dimethoxyquinazolin-4(3H)-one (5.0 g, 24 mmol) inDMF (100 mL) was added 1-chloro-2-iodoethane (3.48 mL, 48.5 mmol)dropwise at 50° C., and the mixture was stirred overnight.

Water was added, the mixture was extracted with ethyl acetate.

The organic layer was dried (Na₂SO₄), concentrated and purified byautomated silica gel chromatography (10% MeOH in DCM) to afford compound146a (6.5 g, 96% yield) as a yellow solid. LCMS: (M+H)⁺: 269.0.

Step (2): Compound 146a→Compound 146b

Compound 146b: 3-(2-chloroethyl)-6,7-dihydroxyquinazolin-4(3H)-one

To a solution of compound 146a in DCM (100 mL) was added BBr₃ dropwiseat −70° C., and the mixture was allowed to warm up to room temperatureand stirred for 1 h. MeOH was added to the mixture dropwise at 0° C.,and then the solvent was removed in vacuo. The residue was purified bysilica gel chromatography (20% MeOH in DCM) to afford compound 146b (5.7g, 91% yield). LCMS: (M+H)⁺: 241.2.

Step (3): Compound 146b→Compound 146c

Compound 146c:3-(2-chloroethyl)-6,7-bis((4-methoxybenzyl)oxy)quinazolin-4(3H)-one

To a solution of 1-(chloromethyl)-4-methoxybenzene (14.8 g, 95.0 mmol)in DMF (100 mL) was added potassium carbonate (16.4 g, 118 mmol) and1-(chloromethyl)-4-methoxybenzene (14.8 g, 95.0 mmol), and this mixturewas stirred at 50° C. overnight. Water was added, and the mixture wasextracted with ethyl acetate. The organic layer was dried (Na₂SO₄),filtered, and concentrated, and the residue was purified using silicagel chromatography (Combiflash RF) to afford compound 146c (7.8 g, 69%yield). LCMS: (M+H)⁺: 480.9.

Step (4): Compound 146c→Compound 146d

Compound 146d:6,7-bis((4-methoxybenzyl)oxy)-3-(2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one

To a solution of compound 146c (7.00 g, 14.6 mmol) in DCM (150 mL) wereadded DIPEA (6.36 mL, 36.4 mmol) and pyrrolidine (3.01 mL, 36.4 mmol),and the mixture was heated to 80° C. The reaction mixture was washedwith 5% NaHCO₃ aq (40 mL), brine, and H₂O, and the organic layer wasdried (Na₂SO₄), filtered, and concentrated, and the residue was purifiedby automated silica gel chromatography (20% MeOH in DCM) to affordcompound 146d (2.9 g, 39% yield). LCMS: (M+H)⁺: 516.3.

Step (5): Compound X-24+Compound 146d→Compound I-146

Compound I-146(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Sodium salt

This compound was prepared according to the two-step sequence of Example143, using compound 146d and compound X-24.

¹H NMR (400 MHz, D₂O) δ ppm 1.37 (s, 3H) 1.39 (s, 3H) 1.47 (d, J=7.07Hz, 3H) 2.13 (br. s., 4H) 3.35-3.60 (m, 5H) 3.68 (d, J=10.61 Hz, 1H)3.99 (q, J=6.99 Hz, 1H) 4.19 (d, J=14.15 Hz, 1H) 4.24-4.41 (m, 2H) 5.00(d, J=14.15 Hz, 1H) 5.34 (d, J=5.05 Hz, 1H) 5.69 (d, J=4.80 Hz, 1H) 6.72(s, 1H) 6.86 (s, 1H) 7.11 (s, 1H) 8.00 (s, 1H).

Example 147 Synthesis of Compound I-147

Step (1): 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione→Compound 147a

Compound 147a: 6,7-dimethoxy-1-methylquinazoline-2,4(1H, 3H)-dione

To a suspension of 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione (40.0 g,180 mmol) in anhydrous chloroform (300 mL) was added (E)-trimethylsilylN-(trimethylsilyl)acetimidate (156 mL, 630 mmol), and the mixture wasstirred at room temperature until a clear solution was obtained (2 h).Iodomethane (168 mL, 2700 mmol) was then added. The reaction mixture washeated to reflux temperature for 48 h. After the solution was cooled toroom temperature, sat. NaHCO₃ aq (30 mL) was added, and the precipitatewas collected by filtration to afford compound 147a (38 g, 89% yield) asa white solid. LCMS: (M+H)⁺: 237.1.

Step (2): Compound 147a→Compound 147b

Compound 147b:3-(2-chloroethyl)-6,7-dimethoxy-1-methylquinazoline-2,4(1H,3H)-dione

To a solution of compound 147a (28.0 g, 119 mmol) in DMF (20 mL) wasadded cesium carbonate (77.0 g, 237 mmol), followed by1-chloro-2-iodoethane (21.6 mL, 237 mmol). The reaction mixture wasstirred at 50° C. overnight. Water was added and the mixture was stirredat rt for 15 min. The white precipitate was collected by filtration andwashed with water to afford compound 147b (29 g, 82% yield). The crudemixture was used in next Step without purification. LCMS: (M+H)⁺: 299.0.

Step (3): compound 147b→Compound 147c

Compound 147c5-chloro-3-(2-chloroethyl)-6,7-dimethoxy-1-methylquinazoline-2,4(1H,3H)-dione

3-(2-chloroethyl)-6,7-dimethoxy-1-methylquinazoline-2,4(1H,3H)-dionecompound 147b (29 g, 97 mmol) and 1-chloropyrrolidine-2,5-dione(19.5 g, 146 mmol) were suspended in DMF (40 mL) and heated at 95° C.for 0.5 h. Water and ethyl acetate (300 mL) were added to the mixture.The organic phase was separated, and the aqueous phase was extractedwith ethyl acetate (2×300 mL). The combined organic phases were dried,filtered and concentrated. The residue was purified by silica gelchromatography (0-15%, EtOAc in hexane) to afford compound 147c (10 g,31% yield). LCMS: (M+H)⁻: 333.0.

Step (4): compound 147c→Compound 147d

Compound 147d:5-chloro-3-(2-chloroethyl)-6,7-dihydroxy-1-methylquinazoline-2,4(1H,3H)-dione

To a solution of compound 147c (10g, 30.0 mmol) in DCM (25 mL) was addedBBr₃ (14.2 mL, 150 mmol) at −78° C. The mixture was allowed to warm upto rt, and stirred for 2 h. The mixture was diluted with MeOH andstripped several times to afford compound 147d (8.8 g, 96% yield) as ayellow solid. The crude product was used in next Step without furtherpurification. LCMS: (M+H)⁺: 304.9.

Step (5): compound 147d→Compound 147e

Compound 147e:5-chloro-3-(2-chloroethyl)-6,7-bis((4-methoxybenzyl)oxy)-1-methylquinazoline-2,4(1H, 3H)-dione

To a solution of compound 147d (4.40 g, 10.1 mmol) in DMF (120 mL) wasadded cesium carbonate (9.87 g, 30.3 mmol), followed by1-(chloromethyl)-4-methoxybenzene (5.50 mL, 40.4 mmol). The reactionmixture was stirred at 50° C. for 5 h. Water was added and the mixturewas stirred at rt for 15 min. The yellow precipitate was collected byfiltration and washed with water. The crude material was purified byautomated silica gel chromatography, using a 40 g column and elutingwith EA/Hexane (0-30%) to afford compound 147e (2.3 g, 42% yield) as ayellow solid. LCMS: (M+H)⁺: 545.1.

Step (6): compound 147e→Compound 147f

Compound 147f:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-1-methyl-3-(2-(pyrrolidin-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione

A solution, of compound 147e (2.3 g, 4.2 mmol), DIPEA (1.363 g, 10.54mmol), and pyrrolidine (0.750 g, 10.5 mmol) in acetonitrile (100 mL) washeated at reflux temperature for 6 h. Water was added, and the productwas extracted with DCM. The organic phase was washed with NaHCO₃ aq,brine and then dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified by automated silica gel chromatography using a 24g column and eluting with 0-5% MeOH in DCM to afford compound 147f (1 g,41% yield) as a yellow solid. LCMS: (M+H)⁺: 580.3.

Step (7): compound X-24+Compound 147f→Compound I-147

Compound I-147:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(5-chloro-6,7-dihydroxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-step sequence of Example143, using compound 147f and compound X-24.

LCMS: (M+H)⁺: 821.0. ¹H NMR (400 MHz, D₂O) δ ppm 1.38 (s, 3H) 1.40 (s,3H) 1.48 (d, J=6.82 Hz, 3H) 2.12 (br. s., 4H) 3.32 (br. s., 3H)3.35-3.66 (m, 6H) 3.98-4.07 (m, 1H) 4.16-4.36 (m, 3H) 4.98 (d, J=14.15Hz, 1H) 5.37 (d, J=4.80 Hz, 1H) 5.68 (d, J=4.29 Hz, 1H) 6.48 (s, 1H)6.91 (s, 1H).

Example 148 Synthesis of Compound I-148

Step (1): Methyl 2-amino-4,5-difluorobenzoate→Compound 148a

Compound 148a: Methyl 2-amino-3-chloro-4,5-difluorobenzoate

Methyl 2-amino-4,5-difluorobenzoate (40.0 g, 214 mmol) and NCS (25.9 g,194 mmol) were suspended in DMF (10 mL) and heated at 95° C. for 30 min.Water and DCM were added to the mixture. The organic phase wasseparated. The water phase was extracted with DCM (2×10 mL). Thecombined organic phase was dried, filtered and concentrated. Theresulting residue was purified via normal phase chromatography (0-40%EtOAc in hexane) to afford Compound 148a (11 g, 26% yield) as a whitesolid. LCMS: (M+H)⁺: 221.9.

Step (2): compound 148a→Compound 148b

Compound 148b:8-chloro-2-(chloromethyl)-6,7-difluoroquinazolin-4(3H)-one

Hydrogen chloride gas was bubbled through a solution of compound 148a(150 mL, 2380 mmol) until the precipitate that initially formed haddissolved. This mixture was stirred at rt overnight. Water was added tothe reaction mixture, and the resulting precipitate was collected byfiltration and dried under high vacuum to afford Compound 148b (8.0 g,67% yield) as gray solid.

LCMS: (M+H)⁺: 264.9.

Step (3): compound 148b→Compound 148c

Compound 148c:8-chloro-6,7-difluoro-2-(pyrrolidin-1-ylmethyl)quinazolin-4(3H)-one

To a solution of Compound 148b (5.00 g, 18.9 mmol) in DCM (120 mL) wasadded a solution of pyrrolidine (3.90 mL, 47.2 mmol) in DCM dropwise,and this mixture was stirred at rt for 2 h. The reaction mixture waswashed with brine (3×), and the organic layer was dried with Na₂SO₄,filtered, and concentrated to Compound 148c (5.0 g, 88% yield) as awhite solid. LCMS: (M+H)⁺: 300.3.

Step (4): Compound 148c→Compound 148d

Compound 148d:8-chloro-6,7-bis((4-methoxybenzyl)oxy)-2-(pyrrolidin-1-ylmethyl)quinazolin-4(3H)-one

A mixture of (4-methoxyphenyl)methanol (46.1 g, 334 mmol) and Compound148c (5.00 g, 16.7 mmol) was heated at 80° C. over the weekend. Waterwas added to the reaction mixture, and the pH was adjusted to 2 using 2N HCl aq, and the product was extracted with DCM. The organic layer waswashed with brine and concentrated, and the residue was purified byautomated reverse phase chromatography (70% MeCN in H₂O containing 0.1%TFA). The combined fractions were then neutralized using 2 N NaOH, andthe product was extracted with DCM. The organic layer was dried,filtered, concentrated and then repurified by automated silica gelchromatography to afford Compound 148d (350 mg, 3.9% yield).

LCMS: (M+H)⁺: 536.0.

Step (5): Compound X-24+Compound 148d→Compound I-148

Compound I-148:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((8-chloro-6,7-dihydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 148d and compound X-24.

LCMS: (M+H)⁺: 777.1. ¹H NMR (400 MHz, D₂O) δ ppm 1.35 (s, 9H) 2.14 (br.s., 4H) 3.51-4.03 (m, 6H) 4.43 (q, J=15.49 Hz, 2H) 4.93 (d, J=13.89 Hz,2H) 5.10 (d, J=5.05 Hz, 1H) 5.63 (d, J=4.80 Hz, 1H) 6.86 (s, 1H) 7.29(s, 1H).

Example 149 Synthesis of Compound I-149

Step (1): 2,4,5-trifluorobenzoyl chloride→Compound 149a

Compound 149a: Ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate

A solution of 2,4,5-trifluorobenzoyl chloride (50 g, 257 mmol) intoluene was added dropwise to a solution of triethylamine (107 mL, 771mmol) and ethyl 3-(dimethylamino)acrylate (44.2 g, 308 mmol) in toluene(500 mL). The mixture was stirred at 90° C. for 3 h. The reactionmixture was cooled down and then was washed with water and extractedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford compound 149a (75 g, 97% yield) as brown oil. Thecrude product was used in next Step without further purification. LCMS:(M+H)⁺: 302.0,

Step (2): compound 149a→Compound 149b

Compound 149b: Ethyl6,7-difluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

A solution of compound 149a (70 g, 232 mmol) in ethanol (200 mL) anddiethyl ether (400 mL) was added to methanamine (54.7 mL, 465 mmol).After the mixture was stirred for 2 h at rt, analysis of the mixture byLCMS indicated that the reaction was complete. The reaction mixture wasconcentrated under reduced pressure, the oily residue was dissolved inDMF (500 mL) and potassium carbonate (96.0 g, 697 mmol) was added. Themixture was stirred at 100° C. for 2 h. Cold water was added to thereaction mixture. The resulting precipitate was collected by filtrationand dried to afford compound 149b (45 g, 73% yield). LCMS: (M+H)⁺:267.9.

Step (3): compound 149b→Compound 149c

Compound 149c:6,7-Dimethoxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A mixture of compound 149b (45.0 g, 168 mmol), potassium hydroxide (472g, 8420 mmol) and methanol (1 L) was heated at reflux temperature for 6h. The pH of the solution was adjusted to 2, and the mixture wasconcentrated in vacuo. The obtained residue was triturated with water toafford compound 149c (35 g, 79% yield) as a pale yellow solid. The crudeproduct was used in next Step without further purification. LCMS:(M+H)⁺: 264.0.

Step (4): compound 149c→Compound 149d

Compound 149d:6,7-Dimethoxy-1-methyl-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

A thick, dark solution of compound 149c (35 g, 133 mmol) dissolved insulfuric acid (354 mL, 6648 mmol) was cooled to 0° C. and potassiumnitroperoxous acid (16.1 g, 160 mmol) was added in small portions. Thetemperature of the reaction mixture was maintained below 10° C. by useof an ice-water bath. After the addition was complete, the mixture wasmaintained under 10° C. for 1 h, and was then allowed to warm up to rt.The mixture was stirred at this temperature for 2 h, after which time itwas poured onto ice-water (800 mL). The yellow solid that precipitatedwas collected by filtration, and washed with water and ethanol. Thesolid was dried in vacuo to afford compound 148d (30 g, 73% yield) as apale yellow solid. The crude product was used in next Step withoutfurther purification. LCMS: (M+H)⁺: 337.4

Step (5): compound 149d→Compound 149e

Compound 149e:5-Amino-6,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

A solution of ethyl compound 149d (30 g, 89 mmol) in a mixture ofethanol (300 mL) and water (300 mL) was treated with sodium sulfide.9H₂O(214 g, 892 mmol) for 2 h at 90° C. After the mixture was cooled down,it was poured into cold water, and the solution was adjusted to pH 2.The resulting yellow precipitate was collected by filtration, washedwith water and dried to afford compound 148e (24 g, 97% yield) as ayellow solid. The crude product was used in next Step without furtherpurification.

LCMS: (M+H)⁺: 279.0

Step (6): compound 149e→Compound 149f

Compound 149f:5-Chloro-6-hydroxy-7-methoxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a pale brown suspension of compound 149e (24 g, 69 mmol) in conc. HClaq (120 mL) was added dropwise a solution of sodium nitrosoamide (4.69g, 69.0 mmol) in water (40 mL) at 0° C. The mixture was stirred at 0° C.for 1 h. To the orange suspension was added HCl aq (180 mL), and themixture was heated at 95° C. for 6 h. The reaction mixture was cooleddown to rt and then poured into water, and the precipitate was collectedby filtration and dried to afford compound 149f (13 g, 66% yield) as apale yellow solid. The crude product was used in next Step withoutfurther purification. LCMS: (M+H)⁺: 283.9.

Step (7): compound 149f→Compound 149g

Compound 149g:5-Chloro-6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a solution of compound 149f (17.6 mL, 45.8 mmol) in DCM (300 mL) wasadded BBr₃ (15.2 mL, 160 mmol) at −78° C. The mixture was allowed towarm up to rt, and stirred overnight. The mixture was diluted with MeOHand stripped several times to afford compound 149g (11 g, 89% yield) asa yellow solid. The crude product was used in next Step reaction withoutfurther purification. LCMS: (M+H)⁺: 269.9.

Step (8): compound 149g→Compound 149h

Compound 149h: 4-Methoxybenzyl5-chloro-6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

To a solution of compound 149g (11 g, 40.8 mmol) in DMF (250 mL) wasadded cesium carbonate (39.9 g, 122 mmol), followed by1-(chloromethyl)-4-methoxybenzene (22.2 mL, 163 mmol). The reactionmixture was stirred at 55° C. for 5 h. Water was added, and the mixturewas stirred at rt for 15 min. The yellow precipitate was collected byfiltration and washed with water to afford compound 149h (20 g, 78%yield) as a yellow solid. The crude mixture was used in next Stepwithout purification. LCMS: (M+H)⁺: 630.3.

Step (9): compound 149h→Compound 149j

Compound 149j:5-Chloro-6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a suspension of compound 149h (20.0 g, 31.7 mmol) in a mixture ofmethanol (120 mL) and water (60 mL) was added KOH (3.56 g, 63.5 mmol)portionwise. The resulting mixture was stirred at 90° C. for 3 h. Thereaction mixture was cooled down to rt and concentrated. The residue wasthen diluted with water and the solution was adjusted to pH 1 using 2 NHCl aq. The precipitate was collected by filtration and dried to affordcompound 149j (13.5 g, 83% yield) as a pale yellow solid. The crudeproduct was used in the next Step without further purification. LCMS:(M+H)⁺: 510.2

Step (10): compound 149j→Compound 149k

Compound 149k:5-Chloro-6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide

To a solution of compound 149j (2.0 g, 2.7 mmol) in DMF (100 mL) wereadded HATU (1.03 g, 2.71 mmol) and DIPEA (1.42 mL, 8.12 mmol), and themixture was stirred for 0.5 h. To this mixture was added2-(pyrrolidin-1-yl)ethanamine (0.34 mL, 2.7 mmol). Analysis of thereaction mixture by LCMS indicated that the reaction was complete in 1h. Water was added, and the mixture was extracted with DCM and washedwith brine. The crude material was purified by automated silica gelchromatography using a 24 g column and eluting with 0-20% MeOH/DCM. Thepure product was then washed by sodium bicarbonate aq, and furtherpurified using a 4 g silica gel column and eluting with 0-20% MeOH/DCMto afford compound 149k (1.3 g, 79% yield) as a yellow solid. LCMS:(M+H)⁺: 606.3

Step (11): compound X-24+Compound 149k→Compound I-149

Compound I-149:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(5-chloro-6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamido)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 149k and compound X-24.

LCMS: (M+H)⁺: 777.1. ¹H NMR (400 MHz, D₂O) δ ppm 1.36 (s, 3H) 1.40 (s,3H) 1.47 (br. s., 3H) 1.99-2.22 (m, 4H) 3.27-4.28 (m, 13H) 4.90 (br. s.,1H) 5.37 (d, J=4.80 Hz, 1H) 5.76 (br. s., 1H) 6.47 (br. s., 1H) 6.85 (s,1H) 8.10 (br. s., 1H).

Example 150 Synthesis of Compound I-150

Step (1): 4,5-dihydroxy-2-nitrobenzaldehyde→Compound 150a

Compound 150a: 4,5-Bis((4-methoxybenzyl)oxy)-2-nitrobenzaldehyde

To a solution of 4,5-dihydroxy-2-nitrobenzaldehyde (79.0 g, 431 mmol) inDMF (500 mL) was added K₂CO₃ (179 g, 1300 mmol), followed by1-(chloromethyl)-4-methoxybenzene (129 mL, 949 mmol). The reactionmixture was stirred at 50° C. for 2 h. The mixture was poured intoice-water, and the resulting suspension was filtered to afford a yellowsolid that was dried and used in the next Step without furtherpurification (152 g, 83% yield).

Step (2): compound 150a→Compound 150b

Compound 150b: Methyl 4,5-bis((4-methoxybenzyl)oxy)-2-nitrobenzoate

To a suspension of compound 150a (152 g, 359 mmol) in MeOH (1.2 L) andDCM (300 mL), were added KOH (101 g, 1800 mmol) and I₂ (182 g, 718mmol). The reaction mixture was stirred for 1.5 h. A saturated aqueoussodium bisulphite solution (300 mL) was added, and it was noted that thechestnut color of the mixture disappeared. The organic phase wasconcentrated and then EtOAc (500 mL) was added to the mixture. Theorganic phase was separated, and the aqueous phase was extracted withEtOAc (2×500 mL). The combined organic phase was dried, filtered andconcentrated to afford compound 150b (128 g, 79% yield) as a red oil.LCMS: (M+H)⁺: 454.1.

Step (3): compound 150b→Compound 150c

Compound 150c: Methyl 2-amino-4,5-bis((4-methoxybenzyl)oxy)benzoate

A mixture of compound 150b (128 g, 282 mmol), iron (126 g, 2260 mmol)and ammonium chloride (151 g, 2820 mmol) in water (400 mL) and methanol(1200 mL) was heated at reflux for 1 h. The mixture was filtered, andthe collected solid was washed with DCM. The filtrate was concentratedin vacuo to remove organic solvents. Then DCM (500 mL) was added to theresulting aqueous solution, the organic phase was separated, and theaqueous phase was extracted with DCM (2×300 mL). The combined organicextracts were concentrated to afford compound 150c (100 g, 84% yield) asa grey solid. LCMS: (M+H)⁺: 424.0.

Step (4): compound 150c→Compound 150d

Compound 150d: 2-Amino-4,5-bis((4-methoxybenzyl)oxy)benzoic acid

To a solution of compound 150c (10.0 g, 23.6 mmol) in water (100 mL) andmethanol (100 mL) was added sodium hydroxide (4.72 g, 118 mmol). Themixture was stirred at 80° C. for 1 h. The methanol was removed undervacuum, and citric acid was added to adjust the pH of the solution to 6.The mixture was then extracted with DCM (3×100 mL). The combined organicextracts were washed with water, dried (Na₂SO₄), filtered andconcentrated to afford compound 150d (8.2 g, 85% yield) as a slightyellow solid. LCMS: (M+H)⁺: 410.3.

Step (5): compound 150d→Compound 150e

Compound 150e:2-amino-4,5-bis((4-methoxybenzyl)oxy)-N-(quinuclidin-4-ylmethyl)benzamide

To a solution of compound 150d (3.00 g, 7.33 mmol) in DMF (50 mL) wasadded HATU (3.34 g, 8.79 mmol) and DIPEA (3.84 mL, 22.0 mmol), and theresulting mixture was stirred at rt for 30 min. Then,quinuclidin-4-ylmethanamine (WO2011125966Ai, 1.13 g, 8.06 mmol) wasadded, and the resulting mixture was stirred at rt for 1 h. Water andEtOAc were added to the mixture. The organic phase was separated, theaqueous phase was extracted with EtOAc three times. The combined organicextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated under vacuum. The residue was purified by automated silicagel chromatography (0-10% solvent B in solvent A; solvent A=DCM, solventB=10:90:1 MeOH:DCM:NH₄OH, 40 g column) to afford compound 150e (2.88 g,74% yield) as a brown solid. LCMS: (M+H)⁺: 532.5.

Step (6): compound 150e→Compound 150f

Compound 150f:6,7-bis((4-methoxybenzyl)oxy)-3-(quinuclidin-4-ylmethyl)quinazolin-4(3H)-one

A mixture of compound 150e (2.88 g, 5.42 mmol) and trimethoxymethane(2.97 mL, 27.1 mmol) in methanol (100 mL) was heated to 120° C.overnight. The solvent was removed under vacuum, and the residue waspurified by Combiflash silica gel chromatography (0-10% solvent B insolvent A; solvent A=DCM, solvent B=10:90:1 MeOH:DCM:NH₄OH, 24 gcolumn). The collected brown solid was dissolved in DCM and washed withwater. The organic layer was concentrated, and the residue was furtherpurified by automated silica gel chromatography (0-10% MeOH/DCM, 4 gcolumn) to afford compound 150f (0.68 g, 23% yield) as a white yellowsolid. LCMS: (M+H)⁺: 542.5.

Step (11): compound X-24+Compound 150f→Compound I-150

Compound I-150:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 150f and compound X-24.

LCMS: (M+H)⁺: 783.7. ¹H NMR (400 MHz, D₂O) δ ppm 1.36 (s, 3H) 1.38 (s,3H) 1.40 (d, J=7.07 Hz, 3H) 1.84 (t, J=7.58 Hz, 6H) 3.23-3.47 (m, 6H)3.85-3.99 (m, 4H) 4.48 (d, J=14.40 Hz, 1H) 5.29 (d, J=5.05 Hz, 1H) 5.70(d, J=4.80 Hz, 1H) 6.84 (d, J=2.02 Hz, 2H) 7.25 (s, 1H) 7.91 (s, 1H).

Example 151 Synthesis of Compound I-151

Step (1): Compound 150d→Compound 151a

Compound 151a2-Amino-4,5-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide

To a solution of compound 150d (1.57 g, 3.83 mmol) in MeCN (20 mL) wereadded HATU (1.60 g, 4.22 mmol) and DIPEA (1.27 mL, 7.67 mmol). Themixture was stirred for 0.5 h, and then 2-(pyrrolidin-1-yl)ethanamine(0.58 mL, 4.6 mmol) was added. The mixture was stirred for 1 h, and thena standard aqueous work-up afforded compound 151a (1.8 g, 93% yield).The crude product was directly used for the next Step without anypurification.

LCMS: (M+H)⁺: 506.5

Step (2): compound 151a→Compound 151b

Compound 151b:6,7-bis((4-methoxybenzyl)oxy)-3-(2-(pyrrolidin-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione

A mixture of compound 151a (1.8 g, 3.6 mmol) and CDI (1.155 g, 7.120mmol) in THF (30 mL) was heated at reflux temperature for 4 h. Thesolution was cooled down and was partitioned between DCM and water. Theorganic layer was washed with aq NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The crude material was purified by automatedsilica gel chromatography (Combiflash RF), using a 40 g column andeluting with 0-10% MeOH/DCM with each solvent containing 0.1% NEt₃. Thedesired product was washed with water, and further purified by normalphase chromatography, using a 4 g column and eluting with 0-10% MeOH/DCMto afford compound 151b (700 mg, 37% yield) as a yellow solid. LCMS:(M+H)⁺: 532.5

Step (3): compound X-24+Compound 151b→Compound I-151

Compound I-151:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(6,7-dihydroxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 151b and compound X-24.

LCMS: (M+H)⁺: 773.0. ¹H NMR (400 MHz, D₂O) δ ppm 1.38 (s, 3H) 1.40 (s,3H) 1.47 (d, J=7.07 Hz, 3H) 2.10 (br. s., 4H) 3.30-3.64 (m, 6H) 4.02 (q,J=7.07 Hz, 1H) 4.16-4.36 (m, 3H) 4.95 (d, J=14.15 Hz, 1H) 5.34 (d,J=4.55 Hz, 1H) 5.68 (d, J=4.55 Hz, 1H) 6.39 (s, 1H) 6.89 (s, 1H) 7.13(s, 1H).

The compounds shown below were obtained from Compound X-24 and the eachcorresponding amine which was synthesized according to the synthesis inWO2013052568A1 in the same way as example 143.

Example 152 Synthesis of Compound I-152

Compound I-152:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(l-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydrocinnoline-3-carboxamido)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 828.0. ¹H NMR (400 MHz, D₂O) δ ppm 1.32-1.39 (m, 9H) 1.45(d, J=6.82 Hz, 3H) 2.11 (br. s., 4H) 3.29-3.69 (m, 6H) 3.75-3.91 (m, 2H)3.98 (q, J=7.07 Hz, 1H) 4.18 (d, J=14.15 Hz, 1H) 4.41 (q, J=6.99 Hz, 2H)4.94 (d, J=14.15 Hz, 1H) 5.35 (d, J=4.80 Hz, 1H) 5.69 (d, J=4.80 Hz, 1H)6.86 (s, 1H) 6.91 (s, 1H) 7.24 (s, 1H).

Example 153 Synthesis of Compound I-153

Compound I-153:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 826.9. ¹H NMR (400 MHz, D₂O) δ ppm 1.28 (t, J=7.07 Hz, 3H)1.34 (s, 3H) 1.36 (s, 3H) 1.44 (d, J=7.07 Hz, 3H) 2.11 (br. s., 4H)2.99-3.03 (m, 1H) 3.29-3.54 (m, 5H) 3.60 (br. s., 1H) 3.68-3.86 (m, 2H)3.97 (d, J=7.07 Hz, 1H) 4.05 (d, J=7.07 Hz, 2H) 4.16 (d, J=14.15 Hz, 1H)4.93 (d, J=14.15 Hz, 1H) 5.35 (d, J=4.80 Hz, 1H) 5.68 (d, J=4.55 Hz, 1H)6.77 (s, 1H) 6.85 (s, 1H) 7.23 (s, 1H) 8.29 (s, 1H).

Example 154 Synthesis of Compound I-154

Compound I-154:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((6,7-dihydroxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 798.9. ¹H NMR (400 MHz, D₂O) δ ppm 1.36 (s, 3H) 1.38 (s,3H) 1.41 (d, J=7.07 Hz, 3H) 1.82 (t, J=7.58 Hz, 6H) 3.20-3.44 (m, 6H)3.78-3.98 (m, 4H) 4.46 (d, J=14.40 Hz, 1H) 5.29 (d, J=5.05 Hz, 1H) 5.70(d, J=4.80 Hz, 1H) 6.42 (s, 1H) 6.85 (s, 1H) 7.15 (s, 1H).

Example 155 Synthesis of Compound I-155

Step (1): 2-chloro-3,4-dimethoxybenzaldehyde→Compound 155a

Compound 155a: 2-Chloro-3,4-dimethoxy-6-nitrobenzaldehyde

Trifluoromethanesulfonic acid (26.6 mL, 299 mmol) was added to asolution of 2-chloro-3,4-dimethoxybenzaldehyde (20 g, 100 mmol) andpotassium nitrate (30.2 g, 299 mmol) in acetic acid (80 mL) withstirring at 0° C., and the resulting mixture was stirred at roomtemperature overnight. The reaction mixture was then poured into water,neutralized with a saturated aqueous sodium hydrogencarbonate solution.The precipitate was collected by filtration and dried to afford compound155a (19 g, 78% yield).

LCMS: (M+H)⁺: 246.1.

Step (2): compound 155a→Compound 155b

Compound 155b: 2-Chloro-3,4-dimethoxy-6-nitrobenzoic acid

To a solution of compound 155a (19 g, 77 mmol) in THF (100 mL) andt-Butanol (100 mL) was added 2-methylbut-2-ene (387 mL, 774 mmol) at 10°C. Subsequently, a solution of sodium chlorite (21.0 g, 232 mmol) andsodium dihydrogenphosphate (27.8 g, 232 mmol) in water (50 mL) was addeddropwise to the solution and the suspension was stirred vigorously for 1h at rt. The mixture was then diluted with saturated NH₄Cl aq and theproduct was extracted with DCM. The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo to afford a yellow solid that was used in the next Step withoutfurther purification (20 g, 99%). LCMS: (M+H—H₂O)⁺: 244.1.

Step (3): compound 155b→Compound 155c

Compound 155c: 6-Amino-2-chloro-3,4-dimethoxybenzoic acid

A mixture of compound 155b (10 g, 38 mmol) and Pd/C (1.0 g, 38 mmol) inmethanol (100 mL) was stirred overnight under an atmosphere of hydrogen.The mixture was filtered, and the solvent was evaporated to affordcompound 155c (8 g, 90% yield) as a brown solid. LCMS: (M+H)⁺: 232.1.

Step (4): compound 155c→Compound 155d

Compound 155d: 5-Chloro-6,7-dimethoxyquinazolin-4(3H-one

In a 100 mL flask were placed compound 155c (7.0 g, 30 mmol),trimethoxymethane (64.1 g, 604 mmol), ammonium acetate (23.3 g, 302mmol) and methanol (20 mL). The reaction mixture was stirred at 120° C.for 3 h. The reaction mixture was concentrated. Water (100 mL) was addedto the reaction mixture, and the resulting mixture was stirred for 15min and filtered to afford compound 155d (6.5 g, 89% yield) as a browncrystalline product.

LCMS: (M+H)⁺: 241.1.

Step (5): compound 155d→Compound 155e

Compound 155e:5-chloro-3-(2-chloroethyl)-6,7-dimethoxyquinazolin-4(3H)-one

To a solution of compound 155d (3.0 g, 12.5 mmol) in DMF (5 mL) wasadded cesium carbonate (8.12 g, 24.9 mmol), followed by1-chloro-2-iodoethane (2.27 mL, 24.9 mmol). The reaction mixture wasstirred at 50° C. for 0.5 h. Water was added and the mixture was stirredat rt for 15 min. The white precipitate was collected by filtration andwashed with water to afford compound 155e (3 g, 79% yield). The crudemixture was used in next Step without purification. LCMS: (M+H)⁺: 303.2.

Step (6): compound 155e→Compound 155f

Compound 155f:5-Chloro-3-(2-chloroethyl)-6,7-dihydroxyquinazolin-4(3H)-one

To a solution of compound 155e (3.0 g, 9.9 mmol) in DCM (10 mL) wasadded tribromoborane (3.40 mL, 34.6 mmol) at −78° C. The mixture wasallowed to warm up to rt, and was stirred overnight. The mixture wasdiluted with MeOH and concentrated, and this procedure was repeatedseveral times to afford compound 155f (2.5 g, 92% yield). The crudeproduct was used in next Step without further purification. LCMS:(M+H)⁺: 275.1.

Step (7): compound 155f→Compound 155g

Compound 155g:5-chloro-3-(2-chloroethyl)-6,7-bis((4-methoxybenzyl)oxy)quinazolin-4(3H)-one

To a solution of compound 155f (2.5 g, 9.1 mmol) in DMF (30 mL) wasadded K₂CO₃ (5.02 g, 36.4 mmol), followed by1-(chloromethyl)-4-methoxybenzene (5.12 mL, 36.4 mmol). The reactionmixture was stirred at 50° C. for 2 h. Water was added, and the mixturewas stirred at rt for 15 min. The yellow precipitate was collected byfiltration and washed with water to afford compound 155g (4 g, 73%yield) as a yellow solid. The crude mixture was used in next Stepwithout purification. LCMS:

(M+H)⁺: 515.4.

Step (8): compound 155g→Compound 155h

Compound 155h:5-Chloro-6,7-bis((4-methoxybenzyl)oxy)-3-(2-(pyrrolidin-1-ylquinazolin-4(3H)-one

A solution of compound 155g (4.0 g, 7.8 mmol), DIPEA (2.57 mL, 15.5mmol), and pyrrolidine (1.28 mL, 15.5 mmol) in acetonitrile (100 mL) washeated to reflux temperature for 12 h. Water was added to the reactionmixture, which was then extracted with DCM. The organic layer was washedwith NaHCO₃, brine and dried over Na₂SO₄, filtered and concentrated invacuo. The crude material was purified by automated silica gelchromatography using an 80 g column and eluting with 0-5% MeOH in DCMover 45 min, to provide 1 g of pure product as a grey solid.Contaminated fractions were concentrated and washed by MeCN to giveanother 800 mg product, affording a total of 1.8 g product (42% yield).LCMS: (M+H)⁺: 550.5.

Step (9): compound X-24+Compound 155h→Compound I-155

Compound I-155:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(5-chloro-6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)ethyl)pyrrolidin-1-ium-1-yl)methy1)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 155h and compound X-24.

LCMS: (M+H)⁺: 791.4. ¹H NMR (400 MHz, D₂O) δ ppm 1.37 (s, 3H) 1.39 (s,3H) 1.47 (d, J=7.07 Hz, 3H) 2.14 (br. s., 4H) 3.34-3.59 (m, 5H) 3.68(br. s., 1H) 3.99 (q, J=6.65 Hz, 1H) 4.13-4.36 (m, 3H) 5.00 (d, J=14.15Hz, 1H) 5.36 (d, J=4.80 Hz, 1H) 5.70 (d, J=4.80 Hz, 1H) 6.58 (s, 1H)6.87 (s, 1H) 7.99 (s, 1H).

Example 156 Synthesis of Compound I-156 Step (1):

6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-,4-dihydroquinoline-3-carboxylic acid→Compound 156a

Compound 156a:6,7-Bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(quinuclidin-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide

To a solution of 6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-,4-dihydroquinoline-3-carboxylic acid (WO2013052568A1, 3.0 g, 5.5 mmol)in DMF (100 mL) were added HATU (3.13 g, 8.23 mmol) and DIPEA (2.88 mL,16.5 mmol), and the mixture was stirred for 0.5 h.Quinuclidin-4-ylmethanamine (WO2011125966A1, 1.28 mL, 8.23 mmol) wasthen added, and the mixture was stirred for 2 h. Sodium bicarbonate wasadded, and the mixture was stirred for 15 min. The yellow precipitatewas collected by filtration, washed with water and purified by automatedsilica gel chromatography using a 24 g column and eluting with 0-20%MeOH in DCM to afford compound 156a (2 g, 61% yield) as a yellow solid.LCMS: (M+H)⁺: 598.6.

Step (2): compound X-24+Compound 156a→Compound I-156

Compound I-156:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 156a and compound X-24.

LCMS: (M+H)⁺: 839.3. ¹H NMR (400 MHz, D₂O) δ ppm 1.37 (s, 3H) 1.39 (s,3H) 1.43 (d, J=7.07 Hz, 3H) 1.82 (br. s., 6H) 3.17-3.53 (m, 8H) 3.64 (s,3H) 3.89-4.02 (m, 2H) 4.52 (d, J=14.40 Hz, 1H) 5.31 (d, J=4.55 Hz, 1H)5.71 (d, J=4.80 Hz, 1H) 6.64 (br. s., 1H) 6.85 (s, 1H) 7.16 (s, 1H) 8.20(s, 1H).

Example 157 Synthesis of Compound I-157

Compound I-157:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(6,7-dihydroxy-1-methy1-4-oxo-1,4-dihydroquinoline-3-carboxamido)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide(which was synthesized according to the synthesis in WO2013052568A1) andcompound X-24. LCMS: (M+H)⁺: 813.2. H NMR (400 MHz, D₂O) δ ppm 1.34 (s,3H) 1.37 (s, 3H) 1.47 (d, J=6.82 Hz, 3H) 2.11 (br. s., 4H) 3.42 (br. s.,4H) 3.49 (br. s., 3H) 3.56-3.82 (m, 4H) 4.00 (d, J=6.82 Hz, 1H) 4.15 (d,J=14.15 Hz, 1H) 4.95 (d, J=14.15 Hz, 1H) 5.37 (d, J=4.55 Hz, 1H) 5.73(d, J=4.80 Hz, 1H) 6.46 (br. s., 1H) 6.82 (s, 1H) 6.97 (s, 1H) 7.96 (s,1H).

Example 158 Synthesis of Compound I-158

Step (1): compound 155d→Compound 158a

Compound 158a:5-Chloro-3-(3-chloropropyl)-6,7-dimethoxyquinazolin-4(3H)-one

To a solution of compound 155d (2.50 g, 10.4 mmol) in DMF (100 mL) wasadded 1-chloro-3-iodopropane (1.60 mL, 20.8 mmol) dropwise at 50° C.,and the mixture was stirred overnight. Water was added, and the mixturewas extracted with EtOAc. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by automated silicagel chromatography (10% MeOH in DCM) to afford compound 158a (2.0 g, 61%yield) as a yellow solid. LCMS: (M+H)⁺: 316.8.

Step (2): compound 158a→Compound 158b

Compound 158b:5-Chloro-3-(3-chloropropyl)-6,7-dihydroxyquinazolin-4(3H)-one

To a solution of compound 158a (2.0 g, 6.3 mmol) in DCM (100 mL) wasadded boron tribromide (2.98 mL, 31.5 mmol) dropwise at −78° C. Thereaction mixture was allowed to warm up slowly to rt and was stirredovernight. The mixture was diluted with MeOH and concentrated, and thisprocess was repeated three times to afford compound 158b (1.7 g, 93%yield). LCMS: (M+H)⁺: 288.8.

Step (3): compound 158b→Compound 158c

Compound 158c:5-Chloro-3-(3-chloropropyl)-6,7-bis((4-methoxybenzyl)oxy)quinazolin-4(3H)-one

To a solution of compound 158b (3.68 g, 23.5 mmol) in DMF (100 mL) wasadded potassium carbonate (4.06 g, 29.4 mmol) and1-(chloromethyl)-4-methoxybenzene (3.68 g, 23.5 mmol), and this mixturewas stirred at 50° C. overnight. Water was added, and the mixture wasextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The residue was purified by automated silica gelchromatography to afford compound 158c (3 g, 96% yield). LCMS: (M+H)⁺:529.1.

Step (4): compound 158c→Compound 158d

Compound 158d:5-Chloro-6,7-bis((4-methoxybenzyl)oxy)-3-(3-(pyrrolidin-1-yl)propyl)quinazolin-4(3H)-one

To a solution of compound 158c (3.3 g, 6.2 mmol) in MeCN (100 mL) wereadded DIPEA (2.72 mL, 15.6 mmol) and pyrrolidine (1.29 mL, 15.6 mmol),and this mixture was heated to 80° C. Analysis of the reaction mixtureby LCMS indicated that the starting material was not fully consumed.Sodium iodide (1.121 g, 7.480 mmol) was added to the reaction mixture,which was then stirred overnight at the same temperature. The volatileswere removed, and the residue was dissolved in EtOAc, washed with brine,NaHCO₃ aq, and water, dried over Na₂SO₄, filtered and then purified byautomated silica gel chromatography (10% MeOH in DCM) to afford compound158d (0.9 g, 26% yield). LCMS: (M+H)⁺: 564.5.

Step (5): compound X-24+Compound 158d→Compound I-158

Compound I-158:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(3-(5-chloro-6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)propyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 158d and compound X-24.

LCMS: (M+H)⁺: 804.9. ¹H NMR (400 MHz, D₂O) δ ppm 1.27 (d, J=7.07 Hz, 3H)1.34 (s, 3H) 1.36 (s, 3H) 2.06 (br. s., 4H) 2.17 (br. s., 2H) 3.27 (s,2H) 3.31-3.50 (m, 6H) 3.89-4.12 (m, 3H) 5.07 (d, J=4.80 Hz, 1H) 5.57 (d,J=4.80 Hz, 1H) 6.78 (s, 1H) 6.81 (s, 1H) 8.04 (s, 1H).

Example 159 Synthesis of Compound I-159 Step (1):

6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate→Compound159a

Compound 159a: Ethyl6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

To a suspension of ethyl6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate(10.0 g, 20.4 mmol) in DMF (100 mL) was added K₂CO₃ (7.06 g, 51.1 mmol)and iodomethane (3.18 mL, 51.1 mmol). The mixture was stirred at 50° C.for 2 h. Water was added, the precipitate was collected by filtration toafford compound 159a (9 g, 87% yield) as a yellow solid that was usedfor the next Step without further purification.

LCMS: (M+H)⁺: 504.1.

Step (2): compound 159a→Compound 159b

Compound 159b:6,7-Bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a suspension of compound 159a (9.0 g, 17.9 mmol) in a mixture ofmethanol (10 mL) and water (5 mL) was added KOH (5.0 g, 89 mmol)portionwise. The resulting mixture was stirred at 90° C. for 3 h. Thereaction mixture was cooled down to rt and concentrated. The residue wasdiluted with water and the pH of the solution was adjusted to 1 using 2N HCl aq. The precipitate was collected by filtration and dried toafford compound 159b (9 g, 92% yield) as a pale yellow solid. The crudeproduct was used in next Step without further purification. LCMS:(M+H)⁺: 476.4.

Step (3): compound 159b→Compound 159c

Compound 159c:3-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)-6,7-bis((4-methoxybenzyl)oxy)-1-methylguinolin-4(1H)-one

To a solution of compound 159b (3.0 g, 5.5 mmol) in DMF (30 mL) wereadded HATU (3.13 g, 8.23 mmol) and DIPEA (2.88 mL, 16.5 mmol). Themixture was stirred for 0.5 h, and 1,4-diazabicyclo[3.2.2]nonane (1.16mL, 8.23 mmol) was added. The reaction mixture was stirred for 1 h.Water was added and the product was extracted with DCM and washed withsodium bicarbonate. The crude material was purified by automated silicagel chromatography using a 24 g column and eluting with 0-20% MeOH inDCM to afford compound 159c (1.8 g, 56% yield) as a yellow solid. LCMS:(M+H)⁺: 584.6

Step (4): compound X-24+Compound 159c→Compound I-159

Compound I-159:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carbonyl)-1,4-diazabicyclo[3.2.2]nonan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 159c and compound X-24. LCMS: (M+H)⁺: 825.1. ¹H NMR(400 MHz, D₂O) δ ppm 1.33-1.51 (m, 9H) 2.27 (br. s., 4H) 3.31-3.87 (m,10H) 3.92-4.07 (m, 2H) 4.11-4.28 (m, 2H) 4.75-4.80 (m, 1H) 5.32 (d,J=5.05 Hz, 1H) 5.68-5.76 (m, 1H) 6.84-6.90 (m, 1H) 6.98 (br. s., 1H)7.46-7.54 (m, 1H) 7.96-8.06 (m, 1H).

Example 160 Synthesis of Compound I-160

Step (1): compound 149j→Compound 160a

Compound 160a:3-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)-5-chloro-6,7-bis((4-methoxybenzyl)oxy)-1-methylquinolin-4(1H)-one

To a solution of compound 149j (2.5 g, 4.9 mmol) in DMF (50 mL) wereadded HATU (2.80 g, 7.35 mmol) and DIPEA (3.43 mL, 19.6 mmol), and theresulting mixture was stirred at rt for 30 min. Then1,4-diazabicyclo[3.2.2]nonane (0.804 g, 6.37 mmol) was added, and theresulting mixture was stirred at rt for 1 h. Water and EtOAc were addedto the mixture. The organic phase was separated, and the aqueous phasewas extracted with EtOAc three times. The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by automated silica gel chromatography(0-10% solvent Bin solvent A; solvent A=DCM, solventB=10:90:1MeOH:DCM:NH₄OH, 24 g column). The collected brown solid wasdissolved in DCM and washed with water, and then the organic layer wasconcentrated. The residue was further purified by automated silica gelchromatography (0-10% MeOH in DCM, 4 g column) to afford compound 160a(1.17 g, 39% yield) as a brown solid. LCMS: (M+H)⁺: 618.5.

Step (2): compound X-24+Compound 160a→Compound I-160

Compound I-160:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-(5-chloro-6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carbonyl)-1,4-diazabicyclo[3.2.2]nonan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 160a and compound X-24.

LCMS: (M+H)⁺: 859.2. H NMR (400 MHz, D₂O) δ ppm 1.33-1.55 (m, 9H)2.07-2.34 (m, 4H) 3.31-3.91 (m, 11H) 4.20 (br. s., 3H) 4.76 (d, J=6.32Hz, 1H) 5.32 (d, J=4.80 Hz, 1H) 5.72 (d, J=4.80 Hz, 1H) 6.84 (s, 1H)6.85-6.88 (m, 1H) 7.86-7.95 (m, 1H).

Example 161 Synthesis of Compound I-161

Step (1): compound 155d→Compound 147a

Compound 161a: 5-chloro-6,7-dimethoxy-3-methylquinazolin-4(3H)-one

To a mixture of K₂CO₃ (24.5 g, 177 mmol) and compound 155d (21.3 g, 89.0mmol) in DMF (100 mL) was added iodomethane (11.02 mL, 177 mmol) at rt,and the resluting mixture was stirred at 50° C. for 1 h. The mixture wascooled down to room temperature and poured into ice-water (700 mL). Theresulting aqueous mixture was stirred for 15 min and filtered to affordcompound 161a (19.3 g, 86% yield) as a yellow solid. LCMS: (M+H)⁺:255.2.

Step (2): compound 161a→Compound 161b

Compound 161b: 5-chloro-6,7-dihydroxy-3-methylquinazolin-4(3H)-one

To a solution of compound 161a (18.0 g, 70.7 mmol) in DCM (150 mL) wasadded tribromoborane (24.30 mL, 247.0 mmol) at −78° C. The mixture wasallowed to warm up to rt, and stirred overnight. The mixture was dilutedwith MeOH and concentrated, diluted again with MeOH and concentrated,and this procedure was repeated several times to afford compound 161b(16.3 g, 99% yield). LCMS: (M+H)⁺: 227.1.

Step (3): compound 161b→Compound 161c

Compound 161c:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-3-methylquinazolin-4(3H)-one

To a solution of compound 161b (16.3 g, 71.9 mmol) in DMF (250 mL) wasadded K₂CO₃ (29.8 g, 216 mmol), followed by1-(chloromethyl)-4-methoxybenzene (29.4 mL, 216 mmol). Then the reactionmixture was stirred at 50° C. for 2 h. Water was added and the mixturewas stirred at rt for 15 min. The yellow precipitate was collected byfiltration and washed with water to afford compound 161c (40 g, 98%yield). LCMS: (M+H)⁺: 467.2.

Step (4): compound 161c→Compound 161d

Compound 161d: Potassium6-amino-2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoate

To a solution of compound 161c (36 g, 63 mmol) in methanol (300 mL) andwater (200 mL) was added KOH (355 g, 6320 mmol). The mixture was heatedat reflux temperature overnight. The mixture was cooled to rt and water(100 mL) was added. The resulting yellow precipitate was collected byfiltration and washed with water (20 mL). The residue was diluted withdiisopropyl ether and DCM (2:1 ratio, 900 mL), and the solid wascollected by filtration, rinsing with the same solvent mixture (2×60mL), to afford compound 161d (23.6 g, 77% yield) as a light brown solid.

LCMS: (M+H)⁺: 444.2.

Step (5): compound 161ad→Compound 161e

Compound 161e:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-3-(quinuclidin-4-ylmethyl)quinazolin-4(3H)-one

To a mixture of compound 161e (5.0 g, 10.4 mmol) in DMF (25 mL) wereadded trimethoxymethane (56.7 mL, 519 mmol), DIPEA (18.12 mL, 104.0mmol) and quinuclidin-4-ylmethanamine, 2 Hydrochloride (ref:WO2011125966A1, 3.29 g, 15.6 mmol). The mixture was stirred at 115° C.for 6 h. Water was added, and the mixture was extracted with DCM andwashed with 2 N NaOH aq. The organic extract was purified by automatednormal phase chromatography using a 160 g basic alumina column andeluting with 30-80% solvent A in solvent B (solvent A=EtOAc/EtOH/Et₃N,76:24:1 ratio; solvent B=Hexane) to afford compound 161e (3.0 g, 50%yield) as a yellow solid. LCMS: (M+H)⁺: 576.4.

Step (6): compound X-24+Compound 161e→Compound I-161

Compound I-161:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)methyl)quinuclidin-1-ium-1-yl)methy1)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example143, using compound 161e and compound X-24. LCMS: (M+H): 817.4. ¹H NMR(400 MHz, D₂O) δ ppm 1.37 (s, 3H) 1.39 (s, 3H) 1.42 (d, J=7.07 Hz, 3H)1.86 (t, J=7.71 Hz, 6H) 3.25-3.46 (m, 6H) 3.85-4.00 (m, 4H) 4.49 (d,J=14.40 Hz, 1H) 5.30 (d, J=5.05 Hz, 1H) 5.71 (d, J=4.80 Hz, 1H) 6.84(br. s., 1H) 6.86 (s, 1H) 7.96 (s, 1H).

Example 162 Synthesis of Compound I-162 Step (1):

6-amino-2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoate

Compound 162a

Compound 162a:6-amino-2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(quinuclidin-4-ylmethyl)benzamide

To a solution of potassium6-amino-2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoate (5.0 g, 10.4mmol) in acetonitrile (400 mL) were added HATU (3.94 g, 10.4 mmol) andDIPEA (9.06 mL, 51.9 mmol), and the mixture was stirred for 0.5 h at rt.Quinuclidin-4-ylmethanamine, 2 Hydrochloride (WO2011125966A1, 2.65 g,12.5 mmol) was then added, and the mixture was stirred for 1 h at rt.Water was added, and the mixture was extracted with DCM and washed withaq sodium bicarbonate. The crude material was purified by automatedsilica column chromatography using a 24 g column and eluting with 40-90%solvent A in solvent B (solvent A=EtOAc/EtOH/Et₃N, 76:24:1 ratio;solvent B=Hexane) to afford compound 162a (2.46 g, 42% yield) as ayellow solid. LCMS: (M+H)⁺: 566.4.

Step (2): compound 162a→Compound 162b

Compound 162b:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-3-(quinuclidin-4-ylmethyl)quinazoline-2,4(1H,3H)-dione

A mixture of compound 162a (100 mg, 0.177 mmol) and CDI (86 mg, 0.53mmol) in THF (20 mL) was heated to reflux temperature for 24 h. Thesolution was cooled to rt and was partitioned between EtOAc and water.The organic phase was dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified by automated silica gel chromatography usinga 24 g column and eluting with 0-20% MeOH (containing 1% NH₄OH) in DCMto afford compound 162b (100 mg, 96% yield). LCMS: (M+H)⁺: 592.4.

Step (3): compound X-24+Compound 162b→Compound 162c

Compound 162c:1-(((4S,6R,7R)-7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((4-methoxybenzyl)oxy)carbonyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-4-((5-chloro-6,7-bis((4-methoxybenzyl)oxy)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl)quinuclidin-1-ium,Iodide

To a mixture of compound 162b (0.101 g, 0.171 mmol) in DMF (2 mL) at 0°C. was added compound X-24 (0.166 g, 0.188 mmol). The mixture wasstirred at the same temperature over 1 h. The solution was poured intoice-cooled 5% NaCl aq (20 mL) and the resulting slurry was stirred for˜15 min. The solid was collected by filtration, rinsed with water (2×),and dried under high vacuum to afford the desired product as a yellowsolid (0.27 g, 70% yield).

LCMS: (M+H)⁺: 1349.6.

Step (4): compound 162c→Compound I-162

Compound I-162:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

To a solution of compound 162c (0.233 g, 0.102 mmol) in DCM (1 mL) at 0°C. was added anisole (0.11 mL, 1.03 mmol), followed by TFA (0.30 mL,3.89 mmol). The mixture was stirred overnight at rt. Diisopropyl ether(10 mL) was then added. The mixture was stirred for 10 min, and theprecipitate was collected by filtration, and rinsed twice withdiisopropyl ether (2×2 mL) The solid was dissolved in a mixture of MeCN(2 mL), water (2 mL), and 2 M HCl aq (0.5 mL), and HP20SS resin (2 g)was added. The mixture was concentrated to dryness, and the resin wasloaded onto a pre-column containing HP20SS resin (4 g). The pre-columnwas installed on the Combiflash instrument and washed with water (flowrate=75 mL/min) until the eluting fractions were at pH 4.5 (˜5 min). Theproduct was then purified by automated reverse phase chromatography (100g C18 Gold column, 10% MeCN/water for 8 min, then 18% MeCN/water for 15min) to afford(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(53 mg) as an off white solid. This compound was suspended in water(HPLC grade, 10 mL), and cooled to 0° C. To the vigorously stirringsuspension was added 0.1 N NaOH aq slowly using an Eppendorf pipetteuntil the pH of the solution was ˜5.5, and a small piece of dry ice wasadded to quench any excess NaOH. The resulting clear solution was thenfrozen and lyophilized to afford compound I-162 (53 mg, 59% yield) as anoff-white solid. LCMS: (M+H)⁺: 833.1. ¹H NMR (400 MHz, D₂O) δ ppm 1.36(s, 3H) 1.38 (s, 3H) 1.41 (d, J=6.57 Hz, 3H) 1.83 (br. s., 6H) 3.14-3.48(m, 6H) 3.91 (d, J=15.92 Hz, 4H) 4.46 (d, J=13.89 Hz, 1H) 5.30 (br. s.,1H) 5.71 (d, J=4.55 Hz, 1H) 6.17-6.33 (m, 1H) 6.86 (s, 1H).

Example 163 Synthesis of Compound I-163

Step (1): compound 150d→Compound 163a

Compound 163a:2-amino-4,5-bis((4-methoxybenzyl)oxy)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)benzamide

To a solution of compound 150d (4.0 g, 9.8 mmol) in acetonitrile (300mL) were added HATU (4.46 g, 11.7 mmol) and DIPEA (8.53 mL, 48.8 mmol),and the mixture was stirred for 0.5 h at rt.(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine, 2 Hydrochloride(2.499 g, 11.72 mmol) was then added, and the mixture was stirred for 2h at rt. Water was added and the mixture was extracted with DCM andwashed with sodium bicarbonate. The organic extract was purified byautomated silica gel chromatography using a 24 g column and eluting with0-20% MeOH (containing 1% NH₄OH) in DCM to afford compound 163a (3.4 g,66% yield) as a yellow solid. LCMS: (M+H)+: 532.4.

Step (2): compound 163a→Compound 163b

Compound 163b:6,7-Bis((4-methoxybenzyl)oxy)-3-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)quinazolin-4(3H-one

A mixture of compound 163a (1.5 g, 2.8 mmol), trimethoxymethane (30.9mL, 282 mmol) and methanol (30 mL) was heated to 100° C. for 7 d. Waterwas added, and the mixture was extracted with DCM and washed with aqsodium bicarbonate. The organic extract was purified by automated silicagel chromatography using a 24 g column and eluting with 0-15% MeOH(containing 1% NH₄OH) in DCM to afford compound 163b (1.2 g, 79% yield)as a yellow solid.

LCMS: (M+H)⁺: 542.4

Step (3): compound X-24+Compound 163b→Compound I-163

Compound I-163:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-(((1R,5S,8s)-3-(6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)-8-methyl-8-azabicyclo[3.2.1]octan-8-ium-8-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-step sequence of Example162, using compound 163b and compound X-24. LCMS: (M+H)⁺: 783.4. ¹H NMR(400 MHz, D₂O) δ ppm 1.38 (s, 3H) 1.40 (s, 3H) 1.46 (d, J=7.07 Hz, 3H)2.18 (t, J=16.42 Hz, 2H) 2.25-2.36 (m, 2H) 2.37-2.55 (m, 2H) 2.82-3.00(m, 2H) 3.03 (s, 3H) 3.84-4.09 (m, 5H) 4.80-4.92 (m, 1H) 5.35 (d, J=4.80Hz, 1H) 5.71 (d, J=4.80 Hz, 1H) 6.82 (s, 1H) 6.88 (s, 1H) 7.27 (s, 1H)8.09 (s, 1H).

Example 164 Synthesis of Compound I-164

Step (1): 2-amino-4,5-bis((4-methoxybenzyl)oxy)benzoic acid→Compound164a

Compound 164a:3-(1-azabicyclo[2.2.1]heptan-4-ylmethyl)-6,7-bis((4-methoxybenzyl)oxy)quinazolin-4(3H)-one

To a solution of 2-amino-4,5-bis((4-methoxybenzyl)oxy)benzoic acid (1.0g, 2.4 mmol) in DMF (10 mL) were added trimethoxymethane (24.05 mL,220.0 mmol), DIPEA (1.280 mL, 7.33 mmol) and1-azabicyclo[2.2.1]heptan-4-ylmethanamine, 2 Hydrochloride (0.730 g,3.66 mmol). The mixture was stirred at 115° C. for 2 h. Water was added,and the mixture was extracted with DCM and washed with 2 N NaOH aq. Theorganic extract was purified by automated silica gel chromatography,using a 24 g column and eluting with 0-15% MeOH (containing 1% NH₄OH) inDCM to afford compound 164a (0.43 g, 33% yield) as a slightly yellowsolid. LCMS: (M+H)⁺: 528.4.

Step (2): compound X-24+Compound 164a→Compound I-141

Compound I-164:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)methyl)-1-azabicyclo[2.2.1]heptan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-step sequence of Example162, using compound 164a and compound X-24. LCMS: (M+H)⁺: 769.4. ¹H NMR(400 MHz, D₂O) δ ppm 1.36 (s, 3H) 1.38 (s, 3H) 1.41 (d, J=7.07 Hz, 3H)1.90 (br. s., 2H) 2.08 (br. s., 2H) 3.21-3.62 (m, 6H) 3.92 (d, J=7.07Hz, 1H) 4.12 (d, J=14.40 Hz, 1H) 4.27 (br. s., 2H) 4.74-4.77 (m, 1H)5.24 (d, J=4.80 Hz, 1H) 5.65 (d, J=4.80 Hz, 1H) 6.86 (s, 1H) 6.91 (s,1H) 7.34 (s, 1H) 8.03 (s, 1H).

Example 165 Synthesis of Compound I-165

Step (1): compound 161d→Compound 165a

Compound 165a:3-(1-azabicyclo[2.2.1]heptan-4-ylmethyl)-5-chloro-6,7-bis((4-methoxybenzyl)oxy)quinazolin-4(3H)-one

To a mixture of compound 161d (1.0 g, 2.07 mmol) in DMF (10 mL) wereadded trimethoxymethane (20.43 mL, 187.0 mmol), DIPEA (1.09 mL, 6.22mmol) and 1-azabicyclo[2.2.1]heptan-4-ylmethanamine, 2 Hydrochloride(0.620 g, 3.11 mmol). Then, the mixture was stirred at 115° C. for 2 h.Water was added, and the mixture was extracted with DCM and washed with2 N NaOH aq. The crude product was purified by automated silica gelchromatography using a 24 g column and eluting with 0-15% MeOH(containing 1% NH₄OH) in DCM to afford compound 165a (0.36 g, 31% yield)as a slight yellow solid. LCMS: (M+H)⁺: 562.4.

Step (2): compound X-24+Compound 165a→Compound I-165

Compound I-165:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-4-oxoquinazolin-3(4H)-yl)methyl)-1-azabicyclo[2.2.1]heptan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-step sequence of Example162, using compound 165a and compound X-24.

LCMS: (M+H)⁺: 802.8. ¹H NMR (400 MHz, D₂O) δ ppm 1.36 (s, 3H) 1.38 (s,3H) 1.41 (d, J=7.33 Hz, 3H) 1.92 (d, J=16.17 Hz, 2H) 2.08 (br. s., 2H)3.20-3.62 (m, 6H) 3.93 (q, J=6.99 Hz, 1H) 4.11 (d, J=14.40 Hz, 1H) 4.23(s, 2H) 4.75 (s, 1H) 5.26 (d, J=4.80 Hz, 1H) 5.65 (d, J=4.55 Hz, 1H)6.80 (s, 1H) 6.87 (s, 1H) 8.02 (s, 1H).

Example 166 Synthesis of Compound I-166

Step (1): 4-nitrobenzene-1,2-diol→Compound 166a

Compound 166a:4,4′-(((4-nitro-1,2-phenylene)bis(oxy))bis(methylene))bis(methoxybenzene)

To a solution of 4-nitrobenzene-1,2-diol (9.6 g, 62 mmol) in DMF (100mL) was added K₂CO₃ (25.7 g, 186 mmol) followed by1-(chloromethyl)-4-methoxybenzene (21.0 mL, 155 mmol). The reactionmixture was stirred at 50° C. for 2 h. Water was added, and the mixturewas stirred at room temperature for 15 min. The resulting yellowprecipitate was collected by filtration and washed with water to affordcompound 166a (25.8 g, 95% yield) as a yellow solid. This material wasused in the next Step without purification. LCMS: (M+H+Na)⁺: 418.1.

Step (2): compound 166a→Compound 166b

Intermediate 3,4-bis((4-methoxybenzyl)oxy)aniline

Under an atmosphere of nitrogen, a mixture of compound 166a (29.5 g,74.6 mmol), ethanol (150 mL), and water (150 mL) was treated withNa₂S.9H₂O (179 g, 746 mmol) for 2 h at 100° C. The mixture was allowedto cool down, and then was poured into cold water. The resulting yellowprecipitate was collected by filtration, washed with water and dried toafford compound 166b (26.3 g, 96% yield) as a yellow solid. Thismaterial was used in next Step without purification. LCMS: (M+H)⁺:366.1.

Step (3): compound 166b→Compound 166c

Compound 166c:5-(((3,4-bis((4-methoxybenzyl)oxy)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

To a solution of compound 166b (19.5 g, 53.4 mmol) in iPrOH (150 mL) wasadded 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.64 mL,55.9 mmol) at room temperature. The resulting mixture was heated to 80°C. for 20 min. Over this time, the mixture became a thick slurry thatwas difficult to stir. The reaction mixture was cooled to roomtemperature, diluted with a small amount of iPrOH to afford a more fluidslurry, and then filtered through a Büchner funnel rinsing with iPrOH.The collected yellow solid was used in the next Step without furtherpurification. LCMS: (M+H+Na)⁺: 542.2.

Step (4): compound 166c→Compound 166d

Compound 166d: 6,7-bis((4-methoxybenzyl)oxy)quinolin-4 (1H)-one

Diphenylether (60 mL) was heated to a boil using a heating mantle. Solidcompound 166c (14.0 g, 26.9 mmol) was added portionwise, and theresulting solution was heated for 5 min. The mixture was cooled until itwas lukewarm, and then hexane was added. The mixture was stirred well,and then filtered through a Büchner funnel. The collected solid wasagain suspended in hexane, stirred for 30 min, and then filtered toafford compound 166d (11 g, 82% yield). This material was used in thenext Step without further purification. LCMS: (M+H)⁺: 418.1.

Step (5): compound 166d→Compound 166e

Compound 166e:3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one

A slurry of compound 166d (5.10 g, 12.2 mmol) in ethanol (30 mL) washeated to 80° C. for 20 min to aid solubility of the starting material.(Note: the starting material does not completely dissolve at elevatedtemperature, but all clumps are broken up.) The mixture was removed fromthe oil bath to add 1 M sodium hydroxide aq (30.5 mL, 30.5 mmol) andformaldehyde (37% aq solution, 25.5 mL, 342 mmol), and this mixture washeated at 80° C. for 4 h. The reaction mixture was cooled to roomtemperature by adding ice, and the resulting slurry was stirred for 20min to break up the clumps. The product was collected by filtrationthrough a Büchner funnel. The solid was washed with water followed byhexanes, and was dried under vacuum overnight to afford compound 166e(4.69 g, 86% yield) as a tan solid. This material was used withoutpurification. LCMS: (M+H)⁺: 448.2.

Step (6): compound 166e→Compound 166f

Compound 166f:3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-4(1H)-one

To a suspension of sodium hydride (0.326 g, 8.14 mmol) in THF (72.6 mL)was added compound 166e (4.6 g, 7.4 mmol), and the mixture was stirredat room temperature for 30 min. Then, SEMCl (1.44 mL, 8.14 mmol) wasadded, and the mixture was stirred at room temperature for 3 h. Themixture was concentrated onto silica gel, and the resulting residue waspurified by automated silica gel chromatography (100% DCM, then 0-10%MeOH/DCM over 10 min, 40 g column) to afford compound 166f (2.2 g, 51%yield) as a dark brown solid. LCMS: (M+H)⁺: 578.2.

Step (7): compound 166f→Compound 166g

Compound 166g:6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carbaldehyde

To a solution of compound 166f (2.2 g, 3.8 mmol) in DCM (50 mL) wasadded manganese dioxide (4.97 g, 57.1 mmol), and the mixture was stirredat room temperature overnight. The mixture was filtered through a celitecake rinsing with DCM, and the filtrate was concentrated to affordcompound 166g (2.1 g, 96% yield) as a yellow solid. This material wasused in the next Step without purification. LCMS: (M+H)⁺: 576.2.

Step (8): compound 166g→Compound 166h

Compound 166h:6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-4(1H)-one

To a solution of compound 166g (2.1 g, 3.7 mmol) in DCM (40 mL) wasadded pyrrolidine (0.452 mL, 5.47 mmol) and acetic acid (10.4 μL, 0.182mmol), and the homogeneous solution was stirred at room temperature for30 min. Then, NaBH(OAc)₃ (1.55 g, 7.30 mmol) was added, and the mixturewas stirred for 1.5 h. The reaction mixture was diluted with DCM, andthen washed successively with saturated NaHCO₃ (aq), NaOH (aq), andbrine. The organic layer was concentrated, and then MeOH (30 mL) and 5 NNaOH (2 mL) were added. The resulting mixture was stirred at roomtemperature for 0.5 h. The volatiles were removed, and the residue waspurified twice via automated silica gel chromatography to affordcompound 166h (1.65 g, 72% yield) as a pale yellow solid. LCMS: (M+H)⁺:631.3. ¹H NMR (DMSO-d₆): 7.96 (s, 1H), 7.64 (s, 1H), 7.41 (d, J=8.6 Hz,2H), 7.38 (d, J=8.6 Hz, 2H), 6.96 (d, J=6.6 Hz, 2H), 6.94 (d, J=6.6 Hz,2H), 5.61 (s, 2H), 5.19 (s, 2H), 5.12 (s, 2H), 3.76 (s, 3H), 3.75 (s,3H), 3.51 (t, J=8.3 Hz, 2H), 3.47 (s, 2H), 2.44-2.50 (m, 4H), 1.62-1.74(m, 4H), 0.78-0.89 (m, 2H), −0.08 (s, 9H).

Step (9): compound X-24+Compound 166h→Compound I-166

Compound I-166:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((6,7-dihydroxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-step sequence of Example162, using compound 166h and compound X-24. LCMS: (M+H)⁺: 742.1. 742.4.¹H NMR (D₂O): 8.05 (s, 1H), 7.41 (s, 1H), 6.89 (s, 1H), 6.86 (s, 1H),5.70 (d, J=4.8 Hz, 1H), 5.34 (d, J=4.8 Hz, 1H), 4.76-4.83 (m, 2H),4.27-4.44 (m, 2H), 4.11 (d, J=13.9 Hz, 1H), 3.91-4.04 (m, 1H), 3.39-3.55(m, 1H), 3.16-3.34 (m, 3H), 1.96-2.20 (m, 4H), 1.34-1.39 (m, 9H).

Example 167 Synthesis of Compound I-167

Step (1): 6,7-dimethoxyquinolin-4(1H)-one→Compound 167a compound 167a:6,7-dimethoxy-5-nitroquinolin-4(1H)-one

A thick, dark solution of 6,7-dimethoxyquinolin-4(1H)-one (10 g, 48.7mmol) in sulfuric acid (40 mL, 750 mmol) was cooled to 0° C., andpotassium nitrate (4.93 g, 48.7 mmol) was added in small portions,maintaining the temperature below 10° C. After the addition wascomplete, the mixture was stirred for 10 min and was poured ontoice-water (300 mL). A yellow solid precipitated which was collected byfiltration and washed with water and ethanol. The solid was collectedand dried in vacuo to afford compound 167a (13.2 g, 108% yield) as apale yellow solid. This crude material was used in next Step withoutpurification. LCMS: (M+H)⁺: 250.9.

Step (2): compound 167a→Compound 167b

Compound 167b: 5-amino-6,7-dimethoxyquinolin-4(1H)-one

A solution of compound 166a (13.2 g, 52.8 mmol) in EtOH (40 mL) and DCM(80 mL) was placed under vacuum, flushed with an atmosphere of hydrogen,and this process was repeated six times. Then, 10% Pd/C (5.61 g, 5.28mmol) was added. The mixture was stirred for 12 h and then filteredrinsing with generous amounts of ethanol. The filtrate was concentratedto afford compound 167b e (11.3 g, 88% yield) as a yellow solid. LCMS:(M+H)⁺: 220.9.

Step (3): compound 167b→Compound 167c

Compound 167c: 5-chloro-6-hydroxy-7-methoxyquinolin-4(1H)-one

To a stirring mixture of compound 167b (12.2 g, 55.4 mmol) in conc. HClaq (50 mL, 1650 mmol) at 0° C. was added a solution of sodium nitrite(4.01 g, 58.2 mmol) in water (17 mL), dropwise. The mixture was stirredat 0° C. for 10 min, at which point LCMS indicated the formation of adiazo-intermediate having one methoxy group de-methylated. To the orangesuspension was added conc. HCl aq (50 mL), and the resulting mixture washeated to 95° C. for 1 h. The reaction mixture was cooled down to roomtemperature, and was filtered and dried to afford compound 167c (10.2 g,76% yield) as a pale yellow solid. The crude product was used in nextStep without purification. LCMS: (M+H)⁺: 225.9.

Step (4): compound 167c→Compound 167d

Compound 167d: 5-chloro-6,7-dihydroxyquinolin-4(1H)-one

To a solution of compound 167c (9.0 g, 40 mmol) in DCM (100 mL) wasadded tribromoborane (5.66 mL, 59.8 mmol) at −78° C. The mixture wasstirred for 2 h at room temperature. The mixture was diluted with MeOH(50 mL) and concentrated, and this process was repeated five times toafford compound 167d (12.5 g, 148% yield) as a brown solid. Thismaterial was carried forward to the next Step without purification.LCMS: (M+H)⁺: 211.9.

Step (5): compound 167d→Compound 167e

Compound 167e 5-chloro-6,7-bis((4-methoxybenzyl)oxy)quinolin-4 (1H)-one

To a solution of compound 167f (10.5 g, 29.8 mmol) in DMF (100 mL) wasadded K₂CO₃ (8.23 g, 59.5 mmol), followed by1-(chloromethyl)-4-methoxybenzene (8.07 mL, 59.5 mmol). The reactionmixture was stirred at 50° C. for 2 h. Water (200 mL) and DCM (150 mL)were added, and the mixture was stirred at room temperature for 15 min.The aqueous phase was extracted with DCM (two times). The combinedorganic phases were dried, filtered, and concentrated to afford aresidue that was purified via automated normal phase chromatography(0-10% MeOH in DCM) to afford compound 167e (5.3 g, 39% yield) as acrimson solid. LCMS: (M+H)⁺: 452.1.

Step (6): compound 167e→Compound 167f

Compound 167f:5-chloro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one

A slurry of compound 167e (25 g, 55 mmol) in ethanol (200 mL) was heatedto 80° C. to aid solubility of the starting material. (Note: thestarting material does not completely dissolve at elevated temperature,but all clumps are broken up.) The mixture was removed from the oil bathto add 1 M sodium hydroxide (aq) (277 mL, 277 mmol) and formaldehyde(37% aq solution, 82 mL, 1100 mmol), and this mixture was heated at 80°C. for 3 h. The reaction mixture was cooled to room temperature, and theresulting slurry was filtered through a Büchner funnel. The solid waswashed with water, followed by hexanes to afford compound 167f (20.4 g,77% yield) as a tan solid. LCMS: (M+H)⁺: 482.0. ¹H NMR (DMSO-d₆): 11.55(d, J=5.8 Hz, 1H), 7.70 (d, J=5.8 Hz, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.30(d, J=8.8 Hz, 2H), 7.09 (s, 1H), 7.01 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6Hz, 2H), 5.17 (s, 2H), 4.86 (s, 2H), 4.32 (d, J=5.1 Hz, 2H), 3.79 (s,3H), 3.74 (s, 3H).

Step (7): compound 167f→Compound 167g

Compound 167g:5-chloro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-4(H)-one

To a suspension of compound 167f (28 g, 51.1 mmol) in DMF (800 mL) wasadded sodium hydride (2.05 g, 51.1 mmol) and the mixture was stirred atroom temperature for 30 min. Then,(2-(chloromethoxy)ethyl)trimethylsilane (9.05 mL, 51.1 mmol) was added,and the mixture was stirred at room temperature for 1 h. Analysis of thereaction mixture by LC-MS indicated that some starting material wasstill present. Water was added to the reaction mixture, and theprecipitate was collected by filtration. Silica gel and DCM were addedto the precipitate, and the resulting mixture was concentrated andpurified by automated silica gel chromatography (100% DCM, then 0-10%MeOH/DCM) to afford compound 167g (11 g, 19% yield) as a brown oil.LCMS: (M+H)⁺: 612.2.

Step (8): compound 167g→Compound 167h

Compound 167h:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carbaldehyde

To a solution of5-chloro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-4(1H)-one(5.48 g, 6.62 mmol) in DCM (90 mL) was added manganese(IV) oxide (8.64g, 99.0 mmol), and the mixture was stirred at room temperatureovernight. The mixture was filtered through a celite cake, rinsed withDCM, and the filtrate was concentrated in vacuo to afford compound 167h(4.2 g, 80% yield). This material was used in the next Step withoutfurther purification. LCMS: (M+H)⁺: 610.2.

Step (9): compound 167h→Compound 167i

Compound 167i:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxylicacid

To a solution of compound 167h (3.64 g, 4.59 mmol) in THF (140 mL) andt-Butanol (140 mL) was added 2-methylbut-2-ene (22.97 mL, 45.90 mmol) at10° C. Subsequently, a solution of sodium chlorite (1.246 g, 13.78 mmol)and sodium dihydrogenphosphate (1.653 g, 13.78 mmol) in water (45 mL)was added dropwise to the first solution, and the mixture was stirredovernight at room temperature. The mixture was then diluted with satNH₄C1 (aq) and extracted with DCM. The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo to afford compound 167i (2.56 g, 89% yield) as a white solid thatwas used in the next Step without further purification. LCMS: (M+H)⁺:626.1. ¹H NMR (DMSO-d₆): 9.08 (s, 1H), 7.57 (s, 1H), 7.49 (d, J=8.6 Hz,2H), 7.30 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz,2H), 5.91 (s, 2H), 5.33 (s, 2H), 4.95 (s, 2H), 3.79 (s, 3H), 3.75 (s,3H), 3.62 (t, J=8.0 Hz, 2H), 0.88 (t, J=8.0 Hz, 2H), −0.05 (s, 9H).

Step (10): compound 167i→Compound 167j

Compound 167j:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxamide

To a solution of compound 167i (2.20 g, 3.51 mmol) in DMF (50 mL) wasadded HATU (1.60 g, 4.22 mmol) and DIPEA (1.84 mL, 10.5 mmol), and theresulting mixture was stirred at room temperature for 30 min. Then,2-(pyrrolidin-1-yl)ethanamine (0.47 mL, 3.7 mmol) was added, and theresulting mixture was stirred at room temperature for 1 h. Water andEtOAc were added to the mixture, and the aqueous phase was extractedwith EtOAc three times. The combined organic extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresulting residue was purified via automated normal phase chromatography(24 g column, 0-10% solvent B in solvent A; solvent A=DCM, solventB=10:90:1 MeOH:DCM:NH₄OH). The collected solid was dissolved in DCM andwashed with water, and then the organic layer was concentrated in vacuo.The residue was passed through a small (4 g) silica gel column (0-10%MeOH in DCM) to afford compound 167j (1.31 g, 52% yield) as a brownsolid. LCMS: (M+H)⁺: 722.3.

¹H NMR (DMSO-d_(G)): 9.88 (t, J=5.6 Hz, 1H), 8.84 (s, 1H), 7.48 (d,J=8.6 Hz, 2H), 7.45 (s, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.8 Hz,2H), 6.85 (d, J=8.6 Hz, 2H), 5.81 (s, 1H), 5.28 (s, 2H), 4.91 (s, 2H),3.79 (s, 3H), 3.75 (s, 3H), 3.59 (t, J=7.8 Hz, 2H), 3.44 (q, J=6.3 Hz,2H), 2.58 (t, J=6.4 Hz, 2H), 2.44-2.50 (m, 4H), 1.64-1.74 (m, 4H), 0.87(t, J=7.8 Hz, 2H), −0.06 (s, 9H).

Step (11): compound X-24+Compound 167j→Compound I-167

Compound I-167:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(5-chloro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-step sequence of Example162, using compound 167j and compound X-24.

LCMS: (M+H)⁺: 833.2. ¹H NMR (D₂O): 8.26 (br. s., 1H), 6.87 (s, 1H),6.47-6.57 (m, 1H), 5.70 (d, J=4.5 Hz, 1H), 5.35 (d, J=4.5 Hz, 1H), 4.90(d, J=14.9 Hz, 1H), 4.17 (d, J=14.1 Hz, 1H), 3.96 (d, J=5.3 Hz, 1H),3.69-3.90 (m, 2H), 3.56-3.67 (m, 1H), 3.26-3.55 (m, 6H), 2.10 (br. s.,4H), 1.45 (d, J=6.6 Hz, 3H), 1.38 (s, 3H), 1.36 (s, 3H).

Example 168 Synthesis of Compound I-168

Step (1):5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid→Compound 168a

Compound 168a:5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(quinuclidin-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide

To a solution of5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (ref: WO2013052568, 6.11g, 11.7 mmol) andquinuclidin-4-ylmethanamine (1.799 g, 12.83 mmol) in DCM (700 mL) wasadded DIPEA (3.05 mL, 17.5 mmol) and PyBOP (7.28 g, 14.0 mmol) at roomtemperature, and the reaction mixture was stirred overnight. The mixturewas concentrated and the residue was purified via automated silica gelchromatography (120 g column, 0-10% MeOH in DCM), and the isolatedproduct was washed with saturated NaHCO₃ aq, brine, and watersuccessively. The resulting material was eluted through a smaller (24 g)silica gel column (0-10% MeOH in DCM) to afford product (2.28 g, 30%yield) as a white solid. This material was not very reactive in thesubsequent Step and was determined by ¹H NMR to exist in a salt form,presumably with some form of silica gel as the counterion. The materialwas suspended in MeOH and 1 equiv of 5 N NaOH (aq) was added. Themixture was stirred for 15 min and then filtered and rinsed with MeOH toafford compound 168a (1.82 g). LCMS: (M+H)⁺: 646.1. ¹H NMR (DMSO-d₆):10.04 (t, J=6.1 Hz, 1H), 8.74 (s, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.31 (d,J=8.6 Hz, 2H), 7.29 (br. s., 1H), 7.02 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6Hz, 2H), 5.36 (s, 2H), 4.91 (s, 2H), 4.50 (q, J=6.8 Hz, 2H), 3.79 (s,3H), 3.75 (s, 3H), 3.11 (d, J=5.8 Hz, 2H), 2.69-2.79 (m, 6H), 1.28-1.37(m, 9H).

Step (2): compound X-24+Compound 168a→Compound I-168

Compound I-168:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example162, using compound 168a and compound X-24.

LCMS: (M+H)⁺: 887.4. ¹H NMR (D₂O): 8.31 (s, 1H), 6.85 (s, 1H), 6.70 (br.s., 1H), 5.70 (d, J=4.5 Hz, 1H), 5.30 (d, J=4.8 Hz, 1H), 4.52 (d, J=14.1Hz, 1H), 3.99-4.16 (m, 2H), 3.86-3.98 (m, 2H), 3.24-3.50 (m, 8H), 1.83(br. s., 6H), 1.42 (d, J=6.8 Hz, 3H), 1.38 (s, 3H), 1.36 (s, 3H),1.22-1.30 (m, 3H).

Example 169 Synthesis of Compound I-169

Step (1): compound 167i→Compound 169a

Compound 169a:5-chloro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(quinuclidin-4-ylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxamide

To a solution of compound 167i (980 mg, 1.56 mmol) in DMF (25 mL) wasadded HATU (714 mg, 1.88 mmol) and DIPEA (1.09 mL, 6.26 mmol), and theresulting mixture was stirred at room temperature for 30 min. Thenquinuclidin-4-ylmethanamine, 2 Hydrochloride (WO 2011125966A1, 367 mg,1.72 mmol) was added and the resulting mixture was stirred at roomtemperature for 1 h. Water and EtOAc were added to the mixture, and theaqueous phase was extracted with EtOAc three times. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified via automated normalphase chromatography (24 g column, 45-90% solvent B in solvent A;solvent A=hexanes, solvent B=3:1 EtOAc/EtOH containing 2% NH₄OH) toafford the desired product as a brown solid. The 1H NMR of this materialsuggested that the product exists as a salt form. To the solid suspendedin MeOH was added 200 μL of 6 N NaOH aq, at which point the mixturebecame homogeneous. After stirring the solution for 5 min, it was thenpassed through an SCX column, eluting with MeOH. The product was thenrecovered by eluting with MeOH containing 1% NH₄OH. The collectedmaterial was concentrated, then redissolved in MeOH and concentratedanother two times to ensure all the NH₄OH was removed. This processafforded compound 169a (0.896 g, 76% yield) as a brown solid. LCMS:(M+H)⁺: 748.7. ¹H NMR (DMSO-d₆): 9.94 (t, J=6.1 Hz, 1H), 8.86 (s, 1H),7.48 (d, J=8.8 Hz, 2H), 7.46 (s, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.01 (d,J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.82 (s, 2H), 5.28 (s, 2H), 4.91(s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.59 (t, J=8.0 Hz, 2H), 3.13 (d,J=6.1 Hz, 2H), 2.72-2.82 (m, 6H), 1.30-1.40 (m, 6H), 0.87 (t, J=7.8 Hz,2H), −0.06 (s, 9H).

Step (2): compound X-24+Compound 169a→Compound I-169

Compound I-169:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example162, using compound 169a and compound X-24.

LCMS: (M+H)⁺: 859.5. ¹H NMR (D₂O) □: 8.10 (s, 1H), 6.85 (s, 1H), 6.41(s, 1H), 5.71 (d, J=4.8 Hz, 1H), 5.32 (d, J=4.8 Hz, 1H), 4.52 (d, J=14.1Hz, 1H), 3.82-4.03 (m, 2H), 3.29-3.53 (m, 6H), 3.23 (br. s., 2H),1.76-1.89 (m, 6H), 1.43 (d, J=6.8 Hz, 3H), 1.39 (s, 3H), 1.37 (s, 3H).

The compounds shown below were obtained from Compound X-24 and the eachcorresponding amine which was synthesized in the same way as example 163to 169.

Example 170 Synthesis of Compound I-170

Compound I-170:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-1-cyclopropyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 899.5. ¹H NMR (D₂O): 8.29 (s, 1H), 7.14 (s, 1H), 6.85 (s,1H), 5.66-5.73 (m, 1H), 5.70 (d, J=4.8 Hz, 1H), 5.30 (d, J=4.8 Hz, 1H),4.51 (d, J=14.4 Hz, 1H), 3.88-4.00 (m, 2H), 3.30-3.50 (m, 7H), 3.23 (br.s., 2H), 1.82 (br. s., 6H), 1.42 (d, J=6.8 Hz, 3H), 1.38 (s, 3H), 1.36(s, 3H), 1.16 (d, J=6.3 Hz, 2H), 0.92 (br. s., 2H).

Example 171 Synthesis of Compound I-171

Compound I-171:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-(((1R,5S,8s)-3-(5-chloro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)-8-methyl-8-azabicyclo[3.2.1]octan-8-ium-8-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 859.2. ¹H NMR (D₂O): 8.19 (br. s., 1H), 6.88 (s, 1H), 6.54(br. s., 1H), 5.70 (d, J=4.8 Hz, 1H), 5.34 (d, J=4.5 Hz, 1H), 4.07-4.26(m, 1H), 3.91-4.04 (m, 3H), 3.86 (br. s., 1H), 2.98 (br. s., 3H),2.41-2.81 (m, 5H), 2.22-2.40 (m, 3H), 1.90-2.05 (m, 2H), 1.45 (d, J=6.3Hz, 3H), 1.40 (s, 3H), 1.38 (s, 3H).

Example 172 Synthesis of Compound I-172

Compound I-172:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 873.5. ¹H NMR (D₂O) □: 8.11 (br. s., 1H), 6.86 (s, 1H),6.45 (br. s., 1H), 5.71 (d, J=4.0 Hz, 1H), 5.33 (m, 1H), 4.53 (d, J=14.1Hz, 1H), 3.94 (m, 2H), 3.54 (m, 3H), 3.32-3.50 (m, 7H), 3.23 (m, 2H),1.83 (m, 6H), 1.43 (d, J=6.3 Hz, 3H), 1.39 (s, 3H), 1.38 (s, 3H).

Example 173 Synthesis of Compound I-173

Compound I-171:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-(((1R,5S,8s)-3-(5-chloro-6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamido)-8-methyl-8-azabicyclo[3.2.1]octan-8-ium-8-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 873.5. ¹H NMR (D₂O): 8.28 (s, 1H), 6.89 (s, 1H), 6.64 (br.s., 1H), 5.67-5.74 (m, 1H), 5.71 (d, J=4.5 Hz, 1H), 5.35 (d, J=4.5 Hz,1H), 4.64-4.67 (m, 1H), 4.13-4.20 (m, 1H), 3.94-4.05 (m, 3H), 3.83-3.91(m, 1H), 3.68 (s, 3H), 3.01 (s, 3H), 2.58-2.80 (m, 3H), 2.44-2.57 (m,2H), 2.30-2.41 (m, 2H), 1.93-2.06 (m, 3H), 1.46 (d, J=6.8 Hz, 3H), 1.40(s, 3H), 1.38 (s, 3H).

Example 174 Synthesis of Compound I-174

Step (1): compound 166b→Compound 174a

Compound 174a: Diethyl2-(((3,4-bis((4-methoxybenzyl)oxy)phenyl)amino)methylene) malonate

To a solution of compound 166b (100 g, 274 mmol) in iPrOH (800 mL) wasadded diethyl 2-(ethoxymethylene)malonate (60.3 mL, 301 mmol) at roomtemperature. The resulting solution was heated to 80° C. for 40 min.Over this time, the suspension became much thicker and was difficult tostir. The mixture was cooled to room temperature, diluted with a smallamount of iPrOH to make the slurry more fluid, and filtered through aBüchner funnel rinsing with iPrOH to afford compound 174a (140 g, 96%yield). LCMS: (M+H)⁺: 536.4.

Step (2): compound 174a→Compound 174b

Compound 174b: ethyl6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate

Diphenyl ether (167 mL) was heated to a boil using a heating mantle.compound 174a (15.6 g, 29.0 mmol) was added portionwise and theresulting solution was heated for 10 min. The resulting dark solutionwas cooled to room temperature, diluted with hexane. This entireprocedure was performed 8 more times (a total of 140 g of startingmaterial was processed), and the hexane mixtures from each batch werecombined and filtered to afford crude product as a grey solid. The solidwas diluted again with hexane, and the resulting slurry was stirred for30 min and filtered. The collected solid was diluted with MeOH, heatedto 80° C. for 30 min, and then filtered to afford compound 174b (75 g,59% yield) LCMS: (M+H)⁺: 490.3.

Step (3): compound 174b→Compound 174c

Compound 174c: ethyl6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxylate

To a suspension of compound 174b (20.0 g, 40.9 mmol) in THF (300 mL) wasadded K₂CO₃ (8.47 g, 61.3 mmol) and SEMCl (7.97 ml, 44.9 mmol). Themixture was stirred at room temperature for 3 h. Water was added to themixture and the THF was evaporated. The remaining mixture was extractedwith DCM (3×200 mL). The combined organic phases were dried, filteredand concentrated to afford compound 174c (23 g, 91% yield) as a dark redoil. This material was used in the next Step without purification. LCMS:(M+H)⁺: 620.5.

Step (4): compound 174c→Compound 174d

Compound 174d:6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxylicacid

To a solution of compound 174c (23 g, 37 mmol) in water (200 mL) andMeOH (200 mL) was added NaOH (7.42 g, 186 mmol). The mixture was stirredat 80° C. for 1 h. The methanol was evaporated, and HCl aq was added tothe solution to adjust the pH to 6. The precipitated solid was collectedby filtration to afford compound 174d (19.8 g, 90% yield) as a greysolid. LCMS: (M+H)⁺: 592.2.

¹H NMR (DMSO-d₆): 8.63 (s, 1H), 7.75 (s, 1H), 7.41 (d, J=8.6 Hz, 2H),7.37 (d, J=8.6 Hz, 2H), 7.34 (s, 1H), 6.92-6.97 (m, J=8.6 Hz, 2H),6.92-6.97 (m, J=9.0 Hz, 2H), 5.66 (s, 2H), 5.19 (s, 2H), 5.09 (s, 2H),3.76 (s, 3H), 3.75 (s, 3H), 3.54 (t, J=7.8 Hz, 2H), 0.84 (t, J=7.8 Hz,2H), −0.07 (s, 9H).

Step (5): compound 174d→Compound 174e

Compound 174e:3-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)-6,7-bis((4-methoxybenzyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-4(1H)-one

To a solution of compound 174d (24.0 g, 40.6 mmol) in DMF (250 mL) wasadded HATU (18.5 g, 48.7 mmol) and DIPEA (28.3 mL, 162 mmol), and theresulting mixture was stirred at room temperature for 30 min. Then,1,4-diazabicyclo[3.2.2]nonane (5.63 g, 44.6 mmol) was added, and themixture was stirred at room temperature for 1 h. Water and EtOAc wereadded and the aqueous phase was extracted with EtOAc three times. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified via normalphase chromatography (24 g column, 0-10% solvent B in solvent A; solventA=DCM, solvent B=10:90:1 MeOH:DCM:NH₄OH). The isolated solid wasdissolved in DCM, washed with water, and then the organic later wasconcentrated. The residue was eluted through a small silica gel column(4 g, 0-10% MeOH/DCM) to afford compound 174e (16.4 g, 58% yield) as abrown solid. LCMS: (M+H)⁺: 700.6. ¹H NMR (DMSO-d₆): 8.22 (s, 1H), 7.67(s, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.39 (d, J=9.1 Hz, 2H), 7.35 (s, 1H),6.95 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.63 (s, 2H), 5.21 (s,2H), 5.14 (s, 2H), 4.53 (br. s., 1H), 3.76 (s, 6H), 3.46-3.59 (t, J=8.1Hz, 2H), 3.36-3.42 (m, 1H), 2.78-3.04 (m, 6H), 1.43-2.02 (m, 4H),0.88-1.34 (m, 3H), 0.84 (t, J=8.0 Hz, 2H), −0.07 (s, 9H). Note: Thisintermediate exists as a mixture of amide rotamers, as observed by ¹HNMR. Only the shifts for the major rotamer are reported.

Step (4): compound X-24+Compound 174e→Compound I-174

Compound I-174:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-(6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carbonyl)-1,4-diazabicyclo[3.2.2]nonan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

This compound was prepared according to the two-Step sequence of Example162, using compound 174e and compound X-24.

LCMS: (M+H)⁺: 811.3. ¹H NMR (D₂O) □: 8.00 (s, 1H), 7.42 (s, 1H), 6.91(s, 1H), 6.85 (s, 1H), 5.71 (d, J=4.8 Hz, 1H), 5.32 (d, J=5.1 Hz, 1H),4.77 (br. s., 1H), 4.17 (d, J=14.1 Hz, 1H), 3.87-4.08 (m, 2H), 3.26-3.85(m, 8H), 2.26 (m, 3H), 1.45 (d, J=7.3 Hz, 3H), 1.39 (s, 3H), 1.37 (s,3H). Note: This analog exists as a mixture of amide rotamers, asobserved by ¹H NMR. Only the shifts for the major rotamer are reported.

The compounds shown below were obtained from Compound X-24 and the eachcorresponding amine which was synthesized according to the synthesis inWO2013052568A1 in the same way as above example.

Example 175 Synthesis of Compound I-175

Compound I-175:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)quinuclidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 825.6. ¹H NMR (D₂O): 8.39 (s, 1H), 7.34 (s, 1H), 6.86 (s,1H), 6.68 (br. s., 1H), 5.71 (d, J=4.8 Hz, 1H), 5.31 (d, J=4.5 Hz, 1H),4.50 (d, J=14.4 Hz, 1H), 3.85-4.02 (m, 2H), 3.38-3.54 (m, 3H), 3.22-3.37(m, 5H), 1.82 (br. s., 6H), 1.42 (d, J=6.6 Hz, 3H), 1.39 (s, 3H), 1.37(s, 3H).

Example 176 Synthesis of Compound I-176

Compound I-176:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-(2-(6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)ethyl)pyrrolidin-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 799.6. ¹H NMR (D₂O): 8.19 (s, 1H), 7.14 (s, 1H), 6.84 (s,1H), 6.63 (s, 1H), 5.70 (d, J=4.5 Hz, 1H), 5.35 (d, J=4.8 Hz, 1H), 4.91(d, J=14.1 Hz, 1H), 4.16 (d, J=14.4 Hz, 1H), 3.92-4.01 (m, 1H),3.66-3.88 (m, 2H), 3.56-3.65 (m, 1H), 3.31-3.52 (m, 5H), 1.98-2.19 (m,4H), 1.45 (d, J=7.1 Hz, 3H), 1.37 (s, 3H), 1.35 (s, 3H).

Example 177 Synthesis of Compound I-177

Compound I-177:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-(5-chloro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carbonyl)-1,4-diazabicyclo[3.2.2]nonan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

LCMS: (M+H)⁺: 845.3. ¹H NMR (D₂O): 7.87 (br. s., 1H), 6.84 (s, 1H), 6.70(br. s., 1H), 5.71 (d, J=4.8 Hz, 1H), 5.31 (d, J=4.8 Hz, 1H), 4.74-4.81(m, 1H), 4.14-4.28 (m, 2H), 3.92-4.08 (m, 1H), 3.28-3.91 (m, 8H),2.03-2.34 (m, 4H), 1.44 (d, J=7.1 Hz, 3H), 1.38 (s, 3H), 1.36 (s, 3H).Note: This analog exists as a mixture of amide rotamers, as observed by¹H NMR. Only the shifts for the major rotamer are reported.

Example 178 Synthesis of Compound I-178

Step (1): compound 167i→Compound 178a

Compound 178a:N-(1-azabicyclo[2.2.1]heptan-4-ylmethyl)-5-chloro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxamide

To a solution of compound 167i (2.56 g, 3.27 mmol) in DMF (80 mL) wasadded HATU (1.49 g, 3.92 mmol) and DIPEA (2.29 mL, 13.1 mmol), and theresulting mixture was stirred at room temperature for 30 min. Then,1-azabicyclo[2.2.1]heptan-4-ylmethanamine, 2 Hydrochloride (WO2011125966A1, 0.716 g, 3.60 mmol) was added, and the resulting mixturewas stirred at room temperature for 1 h. Water and EtOAc were added tothe mixture, and the aqueous phase was extracted with EtOAc three times.The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified on aCombiflash instrument using a Biotage KP-NH column (45-90% 3:1EtOAc/EtOH in hexanes) to afford compound 178a (560 mg, 23% yield) as apale yellow solid. LCMS: (M+H)⁺: 734.4. ¹H NMR (DMSO-d₆): 10.01 (t,J=5.8 Hz, 1H), 8.87 (s, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.46 (s, 1H), 7.30(d, J=8.3 Hz, 2H), 7.01 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.82(s, 2H), 5.28 (s, 2H), 4.91 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.67(d, J=5.8 Hz, 2H), 3.55-3.62 (m, 4H), 2.70-2.84 (m, 2H), 2.16 (s, 2H),1.73-1.81 (m, 2H), 1.46-1.58 (m, 2H), 1.13-1.28 (m, 2H), 0.87 (t, J=8.0Hz, 2H), −0.06 (s, 9H).

Step (2): compound X-24+Compound 178a→Compound 178b

Compound 178b:1-(((4S,6R,7R)-7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((4-methoxybenzyl)oxy)carbonyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-4-((5-chloro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxamido)methyl)-1-azabicyclo[2.2.1]heptan-1-ium

To a solution of compound 178a (0.840 g, 1.075 mmol) in DMF (3.60 mL) at0° C., was added a solution of compound X-24 (1.00 g, 1.13 mmol) in DMF(3.60 mL), and the mixture was stirred for 30 min at 0° C. An ice-coldsolution of NaCl (5% aq, 30 mL) was added, and the resulting slurry wasstirred at 0° C. for 15 min, filtered and dried in vacuo to affordcompound 178b (1.64 g, 72% yield). This material was used in the nextStep without purification.

LCMS: (M+H)⁺: 1492.5.

Step (3): compound 178b→Compound 178c

Compound 178c:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)-1-azabicyclo[2.2.1]heptan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of compound 178b (1.64 g, 0.769 mmol) in DCM (15 mL) at−40° C., was added anisole (0.840 mL, 7.69 mmol) and 1 M AlCl₃ innitromethane (7.69 mL, 7.69 mmol). The resulting clumpy mixture wasstirred at 0° C. for 30 min, and a solution of MeCN, water, and 1 N HClaq (1:1:0.25 ratio, 30 mL) was added followed by 30 mL of iPr₂O. Theorganic layer was extracted with a solution of 20% MeCN in 0.5 M HCl aq(2×30 mL). To the combined aqueous layers was added HP20SS resin (8 g),and the mixture was concentrated until all the MeCN was removed. Thissample was filtered through a loading cartridge that was pre-loaded withmore HP20SS resin (15 g). The cartridge was attached to a Combiflash and100% water was eluted through the cartridge until the fractions werepH>4. A reverse phase Combiflash column was attached (100 g C18 column)and the product was eluted using 0-20% MeCN/water for 10 min, and then30% MeCN/water over 15 min. Pure fractions were collected to affordcompound 178c (370 mg, 55% yield). LCMS: (M+H)⁺: 845.3. ¹H NMR(DMSO-d₆): 10.38-10.54 (m, 1H), 9.86 (br. s., 1H), 8.43 (s, 1H), 7.31(br. s., 2H), 6.92 (br. s., 1H), 6.72 (s, 1H), 5.71-5.84 (m, 1H), 5.26(d, J=5.1 Hz, 1H), 4.93 (m, 1H), 3.92-4.00 (m, 1H), 3.81-3.92 (m, 1H),3.48-3.63 (m, 6H), 3.22-3.28 (m, 2H), 1.94-2.10 (m, 2H), 1.71 (br. s.,2H), 1.47 (s, 3H), 1.44 (s, 3H), 1.11-1.33 (m, 3H).

Step (4): compound 178c→Compound I-178

Compound I-178:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((5-chloro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)-1-azabicyclo[2.2.1]heptan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

A vigorously stirring solution of compound 178c (140 mg, 0.164 mmol) inwater (11 mL) and acetonitrile (5.52 mL) was cooled to 0° C. using anice bath, and 0.1 M NaOH aq was added dropwise until the pH was 5.5. Asmall piece of dry ice was added to quench any excess sodium hydroxide,and then the acetonitrile was removed in vacuo. The remaining solutionwas concentrated by lyophilization to afford compound I-178 (139 mg, 97%yield).

LCMS: (M+H)⁺: 845.3. ¹H NMR (D₂O): 8.12 (s, 1H), 6.80 (s, 1H), 6.40 (s,1H), 5.63 (d, J=4.8 Hz, 1H), 5.24 (d, J=4.5 Hz, 1H), 4.75-4.80 (m, 1H),4.15 (d, J=14.7 Hz, 1H), 3.98 (m, 1H), 3.60 (m, 6H), 3.33 (d, J=7.6 Hz,1H), 3.21 (d, J=7.8 Hz, 1H), 2.11 (m, 2H), 1.87 (m, 2H), 1.42 (d, J=6.8Hz, 3H), 1.36 (s, 3H), 1.34 (s, 3H).

Example 179 Synthesis of Compound I-179

Step (1): compound 151d→Compound 179a

Compound 179a:N-(1-azabicyclo[2.2.1]heptan-4-ylmethyl)-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxamide

To a solution of compound 151d (1.00 g, 1.69 mmol) in DMF (25 mL) wasadded HATU (0.771 g, 2.03 mmol) and DIPEA (1.18 mL, 6.76 mmol), and theresulting mixture was stirred at room temperature for 30 min. Then,1-azabicyclo[2.2.1]heptan-4-ylmethanamine (WO 2011125966A1, 0.337 g,1.690 mmol) was added, and the resulting mixture was stirred at roomtemperature for 1 h. Water and EtOAc were added to the mixture, and theaqueous phase was extracted three times with EtOAc. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by automatedchromatography (100% hexanes, then 0-45% 3:1 EtOAc/EtOH in hexanes, 55 gBiotage®KP-NH column) to afford compound 179a (560 mg, 47% yield) as abrown solid. LCMS: (M+H)⁺: 700.4. ¹H NMR (DMSO-d₆): 10.21 (t, J=5.3 Hz,1H), 8.86 (s, 1H), 7.78 (s, 1H), 7.44 (s, 1H), 7.42 (d, J=8.6 Hz, 2H),7.38 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.1 Hz, 2H), 6.96 (d, J=7.8 Hz, 2H),5.81 (s, 2H), 5.23 (s, 2H), 5.18 (s, 2H), 3.76 (s, 3H), 3.75 (s, 3H),3.67 (d, J=5.3 Hz, 2H), 3.55 (t, J=7.8 Hz, 2H), 2.69-2.87 (m, 2H),2.43-2.50 (m, 2H), 2.18 (s, 2H), 1.46-1.62 (m, 2H), 1.21-1.28 (m, 2H),0.83 (t, J=7.8 Hz, 2H), −0.08 (s, 9H).

Step (2): compound X-24+Compound 179a→Compound 179b

Compound 179b:4-((6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxamido)methyl)-1-(((4S,6R,7R)-7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((4-methoxybenzyl)oxy)carbonyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-1-azabicyclo[2.2.1]heptan-1-ium

To a solution of compound 179a (560 mg, 0.784 mmol) in DMF (2.61 mL) at0° C., was added a solution of compound X-24 (729 mg, 0.823 mmol) in DMF(2.61 mL) and the mixture was stirred for 30 min at 0° C. A coldsolution of NaCl (5% aq, 30 mL) was added, and the resulting slurry wasstirred at 0° C. for 15 min, filtered and dried under vacuum to affordcompound 179b (1.15 g, 92% yield). This material was used in the nextStep without purification.

LCMS: (M+H)⁺: 1457.5.

Step (3): compound 179b→Compound 179c

Compound 179c:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)-1-azabicyclo[2.2.1]heptan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of compound 179b (1.13 g, 0.646 mmol) in DCM (15 mL) at−40° C., were added anisole (0.84 mL, 7.7 mmol) and 1 M AlCl₃ innitromethane (6.46 mL, 6.46 mmol). The resulting clumpy mixture wasstirred at 0° C. for 30 min. A mixture of MeCN, water, and 1 N HCl aq(1:1:0.25 ratio, 30 mL) was added, followed by 30 mL of iPr₂O. Theorganic layer was extracted with a solution of 20% MeCN in 0.5 M HCl aq(2×30 mL). To the combined aqueous layers was added HP20SS resin (10 g),and the mixture was concentrated to remove the acetonitrile. Theremaining slurry was filtered through a loading cartridge that waspre-loaded with HP20SS resin (20 g). The cartridge was attached to aCombiflash instrument and flushed with 100% water until the fractionswere pH>4. A Yamazen Ultrapack ODS-S-50C glass column was attached, andthe product was eluted with 100% H₂O, 5 min, 0-18% MeCN/H₂O over 30 min,and 18% MeCN/H₂O for 10 min. The purest fractions were collected toafford compound 179c (200 mg, 38% yield). LCMS: (M+H)⁺: 811.4. ¹H NMR(DMSO-d₆): 12.82 (br. s., 1H), 10.53 (t, J=5.3 Hz, 1H), 10.37 (br. s.,1H), 10.06 (br. s., 1H), 9.44 (br. s., 1H), 8.47 (br. s., 1H), 7.52 (s,1H), 7.33 (br. s., 2H), 7.00 (s, 1H), 6.70 (s, 1H), 5.75 (dd, J=7.3, 5.3Hz, 1H), 5.26 (d, J=5.1 Hz, 1H), 4.99-5.18 (m, 1H), 3.91-4.09 (m, 2H),3.43-3.62 (m, 8H), 1.92-2.13 (m, 2H), 1.64-1.78 (m, 2H), 1.46 (s, 3H),1.44 (s, 3H), 1.19-1.38 (m, 3H).

Step (4): compound 179c→Compound I-179

Compound I-179:(4S,6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((4-((6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamido)methyl)-1-azabicyclo[2.2.1]heptan-1-ium-1-yl)methyl)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,Sodium salt

Compound 179c (200 mg, 0.245 mmol) in water (11 mL) and acetonitrile(5.50 mL) was cooled to 0° C. using an ice bath, and 0.2 M NaOH aq wasadded dropwise until the pH was 5.5. A small piece of dry ice was addedto quench any excess sodium hydroxide, and then the acetonitrile wasremoved in vacuo. The remaining solution was concentrated bylyophilization to afford compound 1-179 (203 mg, 99% yield). LCMS:(M+H)⁺: 811.2. ¹H NMR (D₂O): 8.30 (s, 1H), 7.18 (s, 1H), 6.80 (s, 1H),6.64 (s, 1H), 5.61 (d, J=4.8 Hz, 1H), 5.20 (d, J=4.8 Hz, 1H), 4.73-4.78(m, 1H), 4.14 (d, J=14.4 Hz, 1H), 3.97 (q, J=7.3 Hz, 1H), 3.64 (d, J=6.8Hz, 2H), 3.42-3.60 (m, 4H), 3.31 (d, J=8.3 Hz, 1H), 3.23 (d, J=8.6 Hz,1H), 2.01-2.20 (m, 2H), 1.79-1.93 (m, 2H), 1.41 (d, J=7.1 Hz, 3H), 1.35(s, 3H), 1.33 (s, 3H).

Example 180 Synthesis of Compound I-180

Step (1): Compound 180a→Compound 180b

Compound 180a (1.45 g, 7.9 mmol) was dissolved into tetrahydrofuran (15mL), and thereto was then added lithium aluminium hydride (0.3 g, 7.9mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. To thereaction mixture was then added sodium sulfate decahydrate at 0° C. Themixture was stirred at rt for 1 hour. To the reaction mixture was thenadded tert-butyl hydrazinecarboxylate (2.1 g, 15.7 mmol). After stirringat room temperature for overnight, the insoluble substance was removedby filtration, and then dissolved ethyl acetate and added saturatedcitric acid aqueous solution. The water phase was separated andextracted with chloroform. The combined organic layer was dried withanhydrous magnesium sulfate. Magnesium sulfate was filtrated off, andthen the liquid was under reduced pressure to yield compound 180b (2.28g, 113%). Compound 180b yielded was used as it was, without beingpurified, in the next reaction.

¹H-NMR (DMSO-D₆) δ: 10.52 (1H, s), 7.55 (1H, s), 2.85-2.77 (2H, m), 2.29(2H, s), 1.78-1.70 (2H, m), 1.42 (9H, s), 1.38 (2H, s), 1.26-1.16 (2H,m).

Step (2): Compound 180b→Compound 180c

The total amount of compound 180b yielded (2.28 g) was dissolved intomethanol (25 mL), and thereto was then added sodium cyanoborohydride(1.2 g, 19.1 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes, and then added 2 mol/L hydrochloric acid aqueous solution untilit gave a pH of 4.0. After stirring at room temperature for 2 hours, themixture was concentrated and thereto was added 8 mol/L sodium hydroxideaqueous solution, and then extracted with ethyl acetate. The combinedorganic layer was dried with anhydrous sodium sulfate. Sodium sulfatewas filtrated off, and then the liquid was under reduced pressure toyield compound 180c (2.99 g, 130%). Compound 180c yielded was used as itwas, without being purified, in the next reaction.

¹H-NMR (DMSO-D₆) δ: 8.22 (1H, s), 4.30 (1H, s), 2.98 (2H, d, J=4.0 Hz),2.75-2.69 (2H, m), 2.47-2.41 (2H, m), 2.14 (2H, s), 1.53-1.38 (13H, m).

Step (3): Compound 180c→Compound 180d

The total amount of compound 180c yielded (2.99 g) was dissolved inmethanol (24 mL), and thereto was then added 4 mol/L hydrochloric acidsolution (23.8 mL, 95 mmol) in 1,4-dioxane at 0° C. After stirring atroom temperature for over night, and the reaction mixture wasconcentrated under reduced pressure. The precipitated solid was thencollected by filtration, and washed with 50% methanol/ethyl acetatesolution to yield compound 180d (2.31 g, 113%)

¹H-NMR (DMSO-D₆) δ: 10.78 (1H, s), 7.45-7.20 (4H, m), 3.28-3.22 (2H, m),3.18 (2H, s), 3.07 (2H, s), 1.97-1.91 (2H, m), 1.72-1.66 (2H, m).

Step (4): Compound X-180d+Compound 180e→Compound 180f

To a suspension of the total amount of compound 180d yielded (2.31 g) in1,4-dioxane (45 mL) was added sodium acetate (3.91 g, 47.7 mmol) andcompound 180e (4.81 g, 11.4 mmol). After stirring at room temperaturefor 1 hour, thereto was stirred at 70° C. for 2 hours. The reactionmixture was diluted with a mixture of ethyl acetate/tetrahydrofuran andaqueous sodium hydroxide solution, then separated and washed with waterand a saturated salt solution, and dried over sodium sulfate. Sodiumsulfate was filtrated off, and then the liquid was concentrated underreduced pressure. The compound-containing liquid was subjected to silicagel column chromatography to elute out the desired compound with ethylacetate (10% triethylamine)/methanol (10% triethylamine). Thedesired-compound-containing fraction was concentrated under reducedpressure to yield compound 180f (1.79 g, 35%).

¹H-NMR (DMSO-D₆) δ: 7.60 (1H, s), 7.49 (1H, s), 7.40-7.36 (4H, m),6.96-6.93 (4H, m), 5.16 (2H, s), 5.15 (2H, s), 4.18 (2H, s), 3.75 (3H,s), 3.75 (3H, s), 2.74-2.68 (2H, m), 2.47-2.41 (2H, m), 2.30 (2H, s),1.57-1.51 (2H, m), 1.20-1.14 (2H, m).

Step (4): Compound X-24+Compound 180f→Compound 180f→Compound I-180

Compound X-24 (886 mg, 1.0 mmol) and compound 180f (544 mg, 1.0 mmol)were used to synthesize the target compound in the same way as Example120.

Yielded amount: 225 mg, (28%)

¹H-NMR (D₂O) δ: 7.47 (1H, s), 7.27 (1H, s), 6.98 (1H, s), 5.76 (1H, d,J=4.3 Hz), 5.37 (1H, d, J=4.3 Hz), 4.88 (1H, d, J=14.4 Hz), 4.34 (2H,s), 4.24 (1H, d, J=14.4 Hz), 4.06 (1H, q, J=7.0 Hz), 3.64-3.43 (6H, m),2.23-2.15 (2H, m), 2.04-1.97 (2H, m), 1.54 (3H, d, J=7.0 Hz), 1.51 (3H,s), 1.49 (3H, s).

LCMS (m+1)=785

The compounds shown in the following tabels can be obtained in the sameway exemplified above.

TABLE 1 Example No. Structure II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

TABLE 2 Example No. Structure II-9 

II-10

II-11

II-12

II-13

II-14

II-15

II-16

TABLE 3 Example No. Structure II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

TABLE 4 Example No. Structure II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

TABLE 5 Example No. Structure II-33

II-34

II-35

II-36

II-37

II-38

II-39

II-40

TABLE 6 Example No. Structure II-41

II-42

II-43

II-44

II-45

II-46

II-47

II-48

TABLE 7 Example No. Structure II-49

II-50

II-51

II-52

II-53

II-54

II-55

Test Example 1

Compound (I) of the invention was evaluated for in vitro antimicrobialactivity thereof.

(Method)

Measurement of Minimum Inhibitory Concentration (MIC: μg/mL) wasconducted according to CLSI (Clinical and Laboratory StandardsInstitute) method, and the amount of bacteria for inoculation was 5×10⁵cfu/mL, and cation-adjusted Iso-Sensitest broth containing humanApo-transferrin was used as a test medium, and the experiment wasconducted using broth microdilution method. The bacteria used are listedbelow.

TABLE 8 Strain Enzyme No. Species Name Produced Strain Type 1 E. ColiJMI1890 PER-1, ESBL producing TEM-1 strain 2 A. baumannii JMI7 PER-1,ESBL and OXA-type OXA-23, carbapenemase 51 producing strain 3 A.baumannii JMI2346 OXA-51, ESBL and OXA-type TEM carbapenemase producingstrain 4 K. pneumoniae SR01358 KPC-2 ESBL and KPC-type carbapenemaseproducing strain

(Results)

The test results are shown in Tables below. The values of inhibitoryactivity are expressed in microgram/mL (μg/ml).

TABLE 9 Com- E. Coli A. baumannii A. baumannii K. pneumoniae poundJMI:890 JMI:7 JMI:2346 SR01358 I-1 1 1 16 ≦0.031 I-3 0.5 0.5 2 ≦0.031I-8 1 1 16 0.25 I-10 1 1 8 ≦0.031 I-11 2 2 16 0.063 I-12 0.25 1 4 ≦0.031I-13 1 2 8 0.063 I-14 1 2 8 ≦0.031 I-15 1 4 16 I-16 0.5 1 8 ≦0.031 I-172 4 16 ≦0.031 I-20 0.063 0.125 0.5 ≦0.031 I-21 0.5 0.5 2 0.063 I-22 0.50.5 4 ≦0.031 I-23 1 1 4 0.063 I-24 2 1 8 0.125 I-25 0.25 0.5 2 ≦0.031I-26 0.5 0.5 4 ≦0.031 I-27 0.5 0.5 4 ≦0.031 I-32 1 0.5 2 0.125 I-33 0.251 4 0.063 I-35 0.5 1 16 ≦0.031 I-36 0.5 0.5 4 0.125 I-37 0.5 1 4 0.125I-38 0.25 0.25 0.5 0.063 I-39 0.25 0.125 1 0.063 I-40 0.5 1 4 0.063 I-411 1 4 0.063 I-42 0.5 0.5 2 0.063 I-43 0.5 1 4 0.063

TABLE 10 Com- E. Coli A. baumannii A. baumannii K. pneumoniae poundJMI:1890 JMI:7 JMI:2346 SR01358 I-51 0.5 2 8 0.125 I-52 0.25 1 4 ≦0.031I-53 0.25 2 4 0.25 I-60 1 1 4 ≦0.031 I-61 2 2 16 0.063 I-62 0.063 0.5 2≦0.031 I-63 1 1 ≦0.031 I-64 0.125 2 4 ≦0.031 I-65 0.125 0.5 2 ≦0.031I-66 0.063 0.25 1 ≦0.031 I-67 0.25 1 2 ≦0.031 I-68 0.5 2 8 ≦0.031 I-690.25 1 8 ≦0.031 I-71 0.25 0.5 2 ≦0.031 I-72 0.125 1 4 ≦0.031 I-73 0.0630.25 2 ≦0.031 I-74 0.25 0.25 4 ≦0.031 I-75 0.125 0.25 4 ≦0.031 I-76 0.250.5 4 ≦0.031 I-77 0.25 0.5 1 ≦0.031 I-78 0.25 0.5 8 ≦0.031 I-83 0.0630.5 2 ≦0.031 I-84 2 1 16 ≦0.031 I-85 0.5 2 8 0.25

TABLE 11 Com- E. Coli A. baumannii A. baumannii K. pneumoniae poundJMI:1890 JMI:7 JMI:2346 SR01358 I-90 1 0.5 8 ≦0.031 I-92 2 4 16 0.125I-94 0.5 1 4 0.063 I-96 0.125 1 8 ≦0.031 I-98 0.063 0.5 4 ≦0.031 I-99 12 16 ≦0.031 I-100 0.125 0.5 1 0.063 I-101 0.063 0.25 0.5 ≦0.031 I-1020.125 0.5 2 ≦0.031 I-103 0.25 0.5 2 ≦0.031 I-104 0.125 1 1 ≦0.031 I-1050.25 2 4 ≦0.031 I-107 0.5 2 4 ≦0.031 I-108 0.5 0.5 2 ≦0.031 I-109 0.5 18 0.063 I-113 0.25 0.25 4 ≦0.031 I-114 0.125 0.5 4 ≦0.031 I-115 0.250.25 2 ≦0.031 I-116 ≦0.031 0.25 1 ≦0.031 I-117 ≦0.031 0.5 1 0.25 I-118≦0.031 0.25 0.5 0.063 I-120 0.063 0.5 2 ≦0.031 I-121 0.063 0.5 2 ≦0.031I-122 0.25 0.5 2 ≦0.031 I-123 0.125 0.5 4 ≦0.031 I-124 0.125 0.5 2≦0.031 I-125 0.125 0.5 8 ≦0.031

TABLE 12 Com- E. Coli A. baumannii A. baumannii K. pneumoniae poundJMI:890 JMI:7 JMI:2346 SR01358 I-4 2 1 ≦0.031 I-54 0.125 0.5 1 ≦0.031I-81 0.5 2 8 ≦0.031 I-126 0.063 0.25 0.5 ≦0.031 I-130 8 ≦0.031 I-1310.125 2 2 0.063 I-132 0.25 1 4 ≦0.031 I-133 0.063 0.5 2 ≦0.031 I-1340.125 1 2 ≦0.031 I-135 0.125 1 4 ≦0.031 I-136 0.5 1 2 ≦0.031 I-137 0.250.5 2 ≦0.031 I-138 0.25 0.5 4 ≦0.031 I-140 0.5 4 ≦0.031 I-142 0.25 0.5 2≦0.031 I-150 2 0.5 2 ≦0.031 I-160 ≦0.031 0.25 0.5 0.063 I-161 0.125 0.254 ≦0.031 I-164 ≦0.031 0.5 2 ≦0.031 I-165 ≦0.031 0.5 1 ≦0.031 I-169 0.0630.25 0.5 ≦0.031 I-174 4 0.25 1 ≦0.031 I-177 0.063 0.25 0.5 ≦0.031 I-180≦0.031 0.5 1 ≦0.031

As shown above, Compounds (I) of the invention have a wide antimicrobialspectrum, in particular, potent antimicrobial spectrum against Gramnegative bacteria, and/or effectiveness against multidrug-resistantbacteria, and further to exhibit high stability against beta-lactamaseproducing Gram negative bacteria.

Formulation Example 1

Powder of a compound of the present invention is formulated to preparean injecting agent.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have a wide antimicrobialspectrum against Gram negative bacteria and Gram positive bacteria, andare effective as an antimicrobial drug having high stability againstbeta-lactamase producing Gram negative bacteria. Moreover, the presentcompounds have good disposition, and high water solubility, and thusparticularly effective as an injecting agent.

1. A compound of the Formula (I):

wherein, R¹ is an optionally substituted carbocyclic group or anoptionally substituted heterocyclic group; R^(2A) and R^(2B) is selectedfrom: a) R^(2A) is hydrogen, optionally substituted amino, —SO₃H,optionally substituted amino sulfonyl, carboxyl, optionally substituted(lower alkyl)oxycarbonyl, optionally substituted carbamoyl, hydroxyl, orsubstituted carbonyloxy; and R^(2B) is hydrogen, provided that R^(2A)and R^(2B) are not hydrogen at the same time, or b) R^(2A) and R^(2B)are taken together to form optionally substituted methylidene oroptionally substituted hydroxyimino; R³ is hydrogen, —OCH₃ or—NH—CH(═O); R^(5A) and R^(5B) is selected from: a) R^(5A) and R^(5B) areeach independently hydrogen, or lower alkyl and R^(5A) and R^(5B) arenot hydrogen at the same time, b) R^(5A) and R^(5B) may be takentogether with the neighboring atom to form optionally substitutedcarbocycle or a optionally substituted heterocyclic group, or c) R^(5A)and R^(5B) may be taken together to form optionally substitutedmethylidene; L is —CH₂—, —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —S—,—CH₂—S—, —CH═CH—S— or —CH═CH—CH₂—S—; E is an optionally substituteddivalent group having at least one quaternary ammonium ion; R¹⁰ ishydrogen or a group represented by the formula (I-B):

wherein, ring A is a benzene ring, monocyclic heterocycle or fusedheterocycle; n is an integer from 0 to 2; each R⁴ is independentlyhydrogen, halogen, oxo, —OH, —CN, —NO₂, —O—C(═O)—R⁹, —C(═O)—R⁹,—C(═O)—OH, —C(═O)—OR⁹, —OR^(9′), —NR⁹R⁹, —SO₂R⁹, —SR⁹, —NR⁹—C(═O)—R⁹,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl;provided that two hydroxyl groups on ring A bind respectively to carbonatoms each adjacently locates; each R⁹ is independently lower alkyl orhalo(lower)alkyl; G is a single bond, optionally substituted loweralkylene, optionally substituted alkenylene or optionally substitutedalkynylene; B is non-existent, a single bond or a 5- or 6-memberedheterocyclic group containing at least 1-3 nitrogen atoms; D isnon-existent, a single bond, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —NR⁶—,—NR⁶—C(═O)—, —C(═O)—NR⁶—, —C(═O)—C(═O)—, —NR⁶—C(═O)—NR⁶—,—C(═O)—C(═O)—NR⁶—, —C(═O)—NR⁶—C(═O)—, —NR⁶—C(═O)—C(═O)—,—NR⁶—NR⁶—C(═O)—, —C(═O)—NR⁶—NR⁶—, —N═N—C(═O)—, —C(═O)—N═N—,—C═N—NR⁶—C(═O)—, —C═N—C(═O)—, —N═C—C(═O)—, —C═N—C(═O)—NR⁶—,—NR⁶—C(═O)—C(═N—OR⁶)—, —C(═N—OR⁶)—C(═O)—NR⁶—, —NR⁶—C(═N—OR⁶)—,—C(═N—OR⁶)—NR⁶—, —C(═O)—C(═N—OR⁶)—, —C(═N—OR⁶)—C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—NR⁶—, —NR⁶—S(═O)₂—, —NR⁶—CH₂—, —CH₂—NR⁶— or —S(═O)₂—;each R⁶ is independently hydrogen or optionally substituted lower alkyl;provided that: when R¹⁰ is hydrogen, E is an optionally substituteddivalent cyclic group having at least one quanternary ammonium ion andat least two hydroxyl groups which bind respectively to carbon atomseach adjacently locates on the cyclic group-; or an ester at carboxylgroup, an amino-protected compound when the amino is present on a ringin the 7-side chain; or a pharmaceutically acceptable salt thereof. 2.The compound of Formula (I) according to claim 1 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereof,wherein R^(5A) is hydrogen and R^(5B) is lower alkyl.
 3. The compound ofFormula (I) according to claim 1 or an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof according toclaim 1, wherein, R¹⁰ is a group represented by the formula (I-B):

wherein each symbol is as defined in claim
 1. 4. The compound of Formula(I) according to claim 1 or an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof according toclaim 1, wherein ring A is a benzene ring or monocyclic heterocycle. 5.The compound of Formula (I) according to claim 1 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein, ring A is fused heterocycle.
 6. Thecompound of Formula (I) according to claim 1 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein: R¹⁰ is hydrogen; and E is an optionallysubstituted divalent cyclic group having at least one quanternaryammonium ion and at least two hydroxyl groups which bind respectively tocarbon atoms each adjacently locates on the cyclic group.
 7. Thecompound of Formula (I) according to claim 1 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereof,wherein: G is a single bond, —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—, —CH₂—CH(CH₃)—, —CH₂—CH(^(i)Pr)- or—CH₂—CH(Ph)-; and wherein ^(i)Pr is isopropyl and Ph is phenyl.
 8. Thecompound of Formula (I) according to claim 1 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereof,wherein: B is non-existent, a single bond or a group represented by theformula:

and the bond of the left side is attached to G and the bond of the rightside is attached to D.
 9. The compound of Formula (I) according to claim1 or an ester at carboxyl group, an amino-protected compound when theamino is present on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof, wherein: D is non-existent, a single bond,—C(═O)—, —O—C(═O)—, —C(═O)—O—, —NR⁶—, —O—, —C(═O)—C(═O),—NR⁶—C(═O)—NR⁶—, —C(═O)—C(═O)—NR⁶—, —C(═O)—NR⁶—C(═O)—,—NR⁶—C(═O)—C(═O)—, —NR⁶—C(═O)—, —C(═O)—NR⁶—, —NR⁶—NR⁶—C(═O)—,—C(═O)—NR⁶—NR⁶—, —N═N—C(═O)—, —C(═O)—N═N—, —C═N—NR⁶—C(═O)—, —C═N—C(═O)—,—N═C—C(═O)—, —C═N—C(═O)—NR⁶—, —NR⁶—C(═O)—C(═N—OR⁶)—,—C(═N—OR⁶)—C(═O)—NR⁶—, —NR⁶—C(═N—OR⁶)—, —C(═O)—C(═N—OR⁶)—,—C(═N—OR⁶)—C(═O)— or —C(═N—OR⁶)—NR⁶—; and wherein R⁶ is as defined inclaim
 1. 10. The compound of Formula (I) according to claim 1 or anester at carboxyl group, an amino-protected compound when the amino ispresent on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof, wherein, the formula (I-C-1):

is a group selected from the following formulae:

wherein: each R^(4a), R^(4b) and R^(4c) is independently hydrogen,halogen, —OH, —CN, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR⁹, optionallysubstituted lower alkyl, or optionally substituted cycloalkyl; each R⁶and R⁹ independently are as defined in claim 1; and the wavy line meansthat the bond is in cis or trans configuration, or a mixture thereof.11. The compound of Formula (I) according to claim 10 or an ester atcarboxyl group, an amino-protected compound when the amino is present onthe ring in the 7-side chain, or a pharmaceutically acceptable saltthereof, wherein, the Formula (I-C-1):

is a group selected from the following formulae:

wherein: R⁶ is hydrogen, methyl, ethyl, tert-buthyl, carboxymethyl,0.2-carboxypropan-2-yl or 1-carboxyethyl; and the wavy line means thatthe bond is in cis or trans configuration, or a mixture thereof.
 12. Thecompound of Formula (I) according to claim 1 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereof,wherein, the formula (I-C-1):

is a group selected from the following formulae:

wherein: each R^(4a) R^(4b) and R^(4d) is independently hydrogen,halogen, —OH, —CN, —C(═O)—R⁹, —C(═O)—OR⁹, —OR⁹, optionally substitutedlower alkyl, or optionally substituted cycloalkyl; and R⁶ and R⁹ are asdefined in claim 1; the wavy line means that the bond is in cis or transconfiguration, or a mixture thereof.
 13. The compound of Formula (I)according to claim 12 or an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof, wherein, the Formula (I-C-1):

is a group selected from the following formulae:


14. The compound of Formula (I) according to claim 1 or an ester atcarboxyl group, an amino-protected compound when the amino is present onthe ring in the 7-side chain, or a pharmaceutically acceptable saltthereof, wherein E is an optionally substituted, saturated orunsaturated, monocyclic or fused cyclic group having at least onequaternary ammonium ion represented by the formula (I-D):

wherein, the dashed line is a bond in the ring; the bond to the cationicnitrogen atom binds to L, and the other bond binds to R¹⁰; provided,when a cationic nitrogen atom binds to R¹⁰, the dashed line is absent,and when a cationic nitrogen atom does not bind to R¹⁰, the dashed lineis a single bond between the cationic nitrogen atom and a neighboringatom or an alkylene group between the cationic nitrogen atom and a ringmember atom other than said neighboring atom.
 15. The compound ofFormula (I) according to claim 1 or an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof accordingto, wherein E is an optionally substituted, saturated or unsaturated,monocyclic or fused cyclic group having at least one quaternary ammoniumion represented by the formula (I-E):

wherein: the bond to the cationic nitrogen atom binds to L, and theother bond binds to R¹⁰; R^(x) is optionally substituted lower alkyl.16. The compound of Formula (I) according to claim 1 or an ester atcarboxyl group, an amino-protected compound when the amino is present onthe ring in the 7-side chain, or a pharmaceutically acceptable saltthereof, wherein L is —S—, —CH₂—S—, —CH═CH—S— or —CH═CH—CH₂—S— and E isan optionally substituted pyridinium group or an optionally substitutedfused pyridinium group.
 17. The compound of Formula (I) according toclaim 16 or an ester at carboxyl group, an amino-protected compound whenthe amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof, E is a group selected from thefollowing formulae which are optionally substituted on the ring;

wherein the bond to the cationic nitrogen atom binds to R¹⁰, the otherbond binds to L.
 18. The compound of Formula (I) according to claim 1 oran ester at carboxyl group, an amino-protected compound when the aminois present on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof according to, wherein E is a group selected fromthe following formulae which are optionally substituted on the ring:

wherein, the bond to the quaternary nitrogen atom binds to L, and theother bond binds to R¹⁰; p is an integer from 1 to 3; n is an integer of1 or 2; R^(x) is optionally substituted lower alkyl.
 19. The compound ofFormula (I) according to claim 13 or an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof, wherein, Eis selected from the group consisting of the formulae (2), (3), (7),(10), (11), (26), (27), (41), (42), (59), (60) and (77).
 20. Thecompound of Formula (I) according to claim 1 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereof,wherein E is a group selected from the following formulae which areoptionally substituted on the ring:

wherein, the bond to the quaternary nitrogen atom binds to L, and theother bond binds to R¹⁰.
 21. The compound of Formula (I) according toclaim 20 or an ester at carboxyl group, an amino-protected compound whenthe amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof, wherein E-R¹⁰ is a groupselected from the following formulae:

wherein, the bond to the quaternary nitrogen atom binds to L.
 22. Thecompound of Formula (I) according to claim 21 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereof,wherein E-R¹⁰ is represented by the formula:

wherein, the bond to the quaternary nitrogen atom binds to L.
 23. Thecompound of Formula (I) according to claim 16 or an ester at carboxylgroup, an amino-protected compound when the amino is present on the ringin the 7-side chain, or a pharmaceutically acceptable salt thereof,wherein -L-E- is represented by the formula;

wherein, the bond to the quaternary nitrogen atom binds to R10, theother bond binds to cephem at 3 position.
 24. The compound of Formula(I) according to claim 1 or an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof, wherein R³is hydrogen or —OCH₃.
 25. The compound of Formula (I) according to claim1 or an ester at carboxyl group, an amino-protected compound when theaminos is present on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof according to, wherein R¹ is an optionallysubstituted phenyl.
 26. The compound of Formula (I) according to claim 1or an ester at carboxyl group, an amino-protected compound when theamino is present on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is represented by the formula:

wherein, X is N, C(—H) or C(—Cl).
 27. The compound of Formula (I)according to claim 26 or an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according, wherein, X is N. 28.The compound of Formula (I) according to claim 26 or an ester atcarboxyl group, an amino-protected compound when the amino is present onthe ring in the 7-side chain, or a pharmaceutically acceptable saltthereof, wherein, X is C(—H) or C(—Cl).
 29. The compound of Formula (I)according to claim 1 or an ester at carboxyl group, an amino-protectedcompound when the amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to wherein, R^(2A) ishydrogen, optionally substituted amino, —SO₃H, optionally substitutedamino sulfonyl, carboxyl, optionally substituted carbamoyl, hydroxyl, orsubstituted carbonyloxy, and R^(2B) is hydrogen.
 30. The compound ofFormula (I) according to claim 1 or an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof accordingto, wherein, R^(2A) is: substituted amino shown below:

substituted amino sulfonyl shown below:

wherein, ring B represents an optionally substituted heterocyclic group;substituted carbamoyl shown below:

wherein, ring B represents an optionally substituted heterocyclic group;or substituted carbonyloxy shown below:

wherein, ring B represents an optionally substituted heterocyclic group.31. The compound of Formula (I) according to claim 1 or an ester atcarboxyl group, an amino-protected compound when the amino is present onthe ring in the 7-side chain, or a pharmaceutically acceptable saltthereof according to, wherein, R^(2A) and R^(2B) are taken together toform: substituted methylidene shown below:

substituted hydroxyimino shown below:

wherein, R⁹ is optionally substituted lower alkyl.
 32. The compound ofFormula (I) according to claim 1 or an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof accordingto, wherein R^(2A) and R^(2B) are taken together to form substitutedhydroxyimino shown below:

wherein, R⁷ and R⁸ are each independently hydrogen, halogen, hydroxyl,carboxyl, optionally substituted lower alkyl, an optionally substitutedcarbocyclic group, or an optionally substituted heterocyclic group, orR⁷ and R⁸ may be taken together with a neighboring atom to form anoptionally substituted carbocyclic group or an optionally substitutedheterocyclic group; Q is a single bond, an optionally substitutedcarbocyclic group or an optionally substituted heterocyclic group; and mis an integer from 0 to
 3. 33. A compound of Formula (I-G-1):

an ester at carboxyl group, an amino-protected compound when the aminois present on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt thereof, wherein, each symbol is as defined above as inclaim
 1. 34. The compound of Formula (I-G-1) according to claim 33 or,an ester at carboxyl group, an amino-protected compound when the aminois present on the ring in the 7-side chain, or a pharmaceuticallyacceptable salt, wherein, R^(5A) is hydrogen and R^(5B) is lower alkyl;R¹⁰ is a group represented by the Formula (I-B);

each symbol is as defined above as in claim
 33. 35. The compound ofFormula (I-G-1) according to claim 33 or, an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof, wherein: Xis C(—H), C(—Cl) or N; each R⁷ and R⁸ is independently hydrogen or loweralkyl; R3 is hydrogen; m is 0 or 1; Q is a single bond; L is —CH2-; E isa group selected from the following formulae;

wherein: Rx is lower alkyl, p is an integer from 1 to 3; G is a singlebond or lower alkylene; B is non-existent, a single bond; D isnon-existent, a single bond, —C(═O)—, —C(═O)—C(═O)—, —NR⁶—C(═O)—C(═O)—,—NR⁶—C(═O)— or —NH—C(═O)—C(═N—OR^(6a)); R⁶ is hydrogen or lower alkyl;R^(6a) is hydrogen, methyl, carboxymethyl, or 2-carboxypropane-2-yl; theformula (1-B-2);

is a group selected from the following formulae;

wherein: each R^(4a), R^(4b) and R^(4c) is independently hydrogen,halogen or lower alkyl; and R^(4d) is hydrogen, lower alkyl or lowercycloalkyl.
 36. A pharmaceutical composition, which comprises a compoundof Formula (I) according to claim 1, an ester at carboxyl group, anamino-protected compound when the amino is present on the ring in the7-side chain, or a pharmaceutically acceptable salt thereof.
 37. Thepharmaceutical composition according to claim 36, which possessesantimicrobial activity.
 38. The compound of Formula (I) according toclaim 1, an ester at carboxyl group, an amino-protected compound whenthe amino is present on the ring in the 7-side chain, or apharmaceutically acceptable salt thereof according to, wherein theFormula (I-C-1) is:

wherein: ring A is defined as a fused heterocycle ring system comprisedof at least two (2) rings fused together; R⁴ optionally is substitutedon each of the at least two (2) rings of the fused heterocycle ringsystem defined as ring A, such that each R4 substituent on each ring ofthe fused heterocycle ring system independently are selected fromidentical or different substituents; wherein: each R⁴ as defined aboveoptionally is substituted independently on each ring of the fusedheterocycle ring is selected from hydrogen, halogen, oxo, —OH, —CN,—NO₂, —O—C(═O)—R⁹, —C(═O)—R⁹, —C(═O)—OH, —C(═O)—OR⁹, —OR^(9′), —NR⁹R⁹,—SO₂R⁹, —SR⁹, —NR⁹—C(═O)—R⁹, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; provided that two hydroxyl groups onring A bind respectively to carbon atoms each adjacently locates; and nis an integer from 0 to
 2. 39. A method for treating bacterialinfections, which comprises administering a compound of Formula (I)according to claim 1 to a subject in need thereof.
 40. The methodaccording to claim 39, wherein the bacterial infections are caused byGram-Negative bacteria or Gram-Positive bacteria.
 41. The methodaccording to claim 39, wherein the compounds of Formula (I) exhibitpotent antimicrobial activity against beta-lactamase producing Gramnegative bacteria;
 42. The method according to claim 39, wherein theGram negative bacteria is selected from: Gram negative bacteria ofenterobacteria selected from E. coli, Klebsiella, Serratia,Enterobacter, Citrobacter, Morganella, Providencia or Proteus; Gramnegative bacteria colonized in respiratory system selected fromHaemophilus, Moraxella; Gram negative bacteria of glucose nonfermentation selected from Pseudomonas aeruginosa, Pseudomonas otherthan P. aeruginosa, Stenotrophomonas, Burkholderia or Acinetobacter;Gram negative multidrug-resistant bacteria selected from Class B typemetallo-beta-lactamase producing Gram negative bacteria, andextended-spectrum beta-lactamase (ESBL) producing bacteria; or Grambeta-lactam drug resistant Gram negative bacteria selected from ESBLproducing bacteria.
 43. The method according to claim 39, wherein theGram positive bacteria is selected from methicillin-resistantStaphylococcus aureus (MRSA) or penicillin-resistant Streptococcuspneumoniae (PRSP).
 44. A method for treating biothreat organisms, whichcomprises administering a compound of Formula (I) according to claim 1to a subject in need thereof.
 45. The method according to claim 43,wherein the biothreat organisms are selected from Yersinia pestis,Bacillus anthracis, Francisella tularensis, Burkholderia malleiBurkholderia pseudomallei, Brucella suis, Brucella melitensis orBrucella abortus.
 46. A method for treating Gram-negative bacterialinfections, which comprises administering a compound of Formula (I)according to claim 1 to a subject in need thereof.
 47. A method fortreating Gram-positive bacterial infections, which comprisesadministering a compound of Formula (I) according to claim 1 to asubject in need thereof.